1. Please check and comment entries here.
Table of Contents

    Topic review

    Inhibition of WHSC1, Prostate Cancer

    Subjects: Oncology
    View times: 6
    Submitted by: Muzamil Yaqub Want

    Definition

    Immunotherapy initially demonstrated promising results in prostate cancer (PCa), but the modest or negative results of many recent trials highlight the need to overcome the poor immunogenicity of this cancer. The design of effective therapies for PCa is challenged by the limited understanding of the interface between PCa cells and the immune system in mediating therapeutic resistance. Prompted by our recent observations that elevated WHSC1, a histone methyltransferase known to promote progression of numerous cancers, can silence antigen processing and presentation in PCa.

    1. Introduction

    Modulating the immune landscape of prostate cancer (PCa) to promote anti-tumor immunity has gained enthusiasm following the initial clinical success of trials testing Provenge and Prostvac VF to stimulate immune responses against prostate acid phosphatase (PAP) and prostate specific antigen (PSA), respectively. While several studies have reported favorable clinical outcomes, especially in patients with therapy-induced immune infiltration, PCa tumors typically show only low-level immune cell infiltration in the tumor microenvironment (TME).
    WHSC1 is a histone methyltransferase that targets histone 3 lysine 36 (H3K36) and, to a lesser extent, histone 4 lysine 20 (H4K20). Elevated WHSC1 expression correlates with worse prognosis in a number of cancers [1][2][3][4][5][6][7] due to its oncogenic role in promoting cell growth and metastases; however, the magnitude of the effect and mechanism(s) of action of WHSC1 remain poorly understood. In studies designed to understand the interplay between PCa cells and the immune system, we recently demonstrated that elevated levels of the WHSC1 enzyme limit lymphocyte infiltration in PCa tumors, reduce antigen processing and presentation, as well as repress local activation of immune pathways [8].
    We previously reported that WHSC1 inhibition increases the frequency of intratumoral CD8+ T cells [8]; however, the changes associated with the overall immune composition of the TME following WHSC1 blockade remain unknown. Here, we broadly investigate the immunological changes in the TME in vivo following pharmacological inhibition of WHSC1and report a phenotypic shift in infiltrating immune cells that reflects both increased cytotoxic T cell activity and local modulation of diverse myeloid cell subsets present within the tumor. Lastly, using pathway analysis of changes resulting from WHSC1 inhibition, we propose a signaling circuitry that defines immune activation and favors a potent anti-tumor response.

    2. Discussion

    We recently demonstrated that WHSC1 inhibition potently increases antigen processing and presentation via an elegant epigenetic remodeling of prostate cancer cells that increases MHC expression and antigen presentation, accompanied by an increase in tumor-infiltrating CD8+ T cells [8]. Interestingly, we also observed that when tumors were grafted in immunodeficient NSG mice, no tumor growth inhibition was observed [8], suggesting that at least part of the anti-tumor effect of MCTP39 was mediated through the activity of a functional immune system. While recognizing that both mouse models were grafted subcutaneously (SQ), it is well established that SQ tumors are still subject to the immune-driven anti-tumor effect in numerous cancer indications [8][9][10][11][12][13][14][15] and include a rich and heterogeneous immune compartment reshaped by therapeutic interventions. For these studies, we used the syngeneic prostate cancer cell line TRAMP C2 [16] that can be grafted in immunocompetent mice, thus permitting tumor-infiltrating immune cells to be broadly profiled in response to therapy.
    Previous studies employing single-cell analyses identified large myeloid and lymphoid infiltrates in the prostate tumors of 13 patients [17], suggesting an interconnected cellular network between tumors and the immune system that may define disease progression. However, on the therapeutic side, there is still limited knowledge regarding the immune signaling events that accompany prostate cancer regression following effective treatment.
    When evaluating the expression of a focused panel of immune genes from bulk data, we identified a significant enrichment in antigen presentation pathways, lymphocyte activation, and migration. Among the most upregulated genes, we saw the ligands Cxcl13, Ccl21a, and Ccl22 and the chemokine receptors Cxcr4 and Ccr7. CCL22 is a homeostatic cytokine that can be produced in response to inflammation and acts through its receptor CCR4 to control immune activation in the lymph node [18][19]. The CCL21/CCR7 axis has a dual role, since it can both regulate the homing of immune cells to the lymph node to prime and activate T cells, B cells, and dendritic cells [20] and be involved in a metastatic tumor phenotype by promoting cancer cells migration [21][22]. In parallel to these functions, CXCL13 plays a key role in promoting immune infiltration in the tumor via binding to CXCR5 and controlling tumor behavior by binding to receptors on the tumor surface [23]. While overall pathway analysis suggested that treatment with MCTP39 enriched gene signatures related to immune functions, immune cell recruitment, and antigen processing and presentation, the origin of the signal and the location of the receptor can determine whether the resulting signaling cascade will lead to a pro-tumorigenic or anti-tumor response. Single cell RNASeq analyses revealed a large infiltrating myeloid cell component, consistent with previous studies of CD45+ cells infiltrating prostate tumors [24][25], and suggested that improving the function of T cells within prostate cancer will necessitate successfully reprogramming the more abundant myeloid cells to promote local inflammation and anti-tumor immunity [26]. Based on our data and the broad and pleiotropic effects of MCTP39 on myeloid cell reprogramming, we propose that MCTP39 has previously underappreciated activity in targeting and modulating multiple simultaneous attributes of myeloid cell biology, which warrants additional investigation.
    To maximize the anti-tumor immune response, the presence and activation of cytotoxic cells is required. Mice that were treated with MCTP39 had a higher frequency of cytotoxic CD8+ T cells and NK cells, positive for Granzyme K, Ifn-γ, and Lamp1/Cd107a. The latter plays a key role in forming cytotoxic granules to be released upon antigen recognition, potentially indicating an ongoing anti-tumor response. The expression of Pdcd1/Cd279/Pd-1 was also increased in CD8+ T cells, and while elevated PD-1 is a marker for exhausted CD8+ T cells, it also defines tumor- and neoantigen-specific T cells. In this case, we also observed a significant reduction in the frequency of CD8+ T cells expressing exhaustion markers including Lag3 [27][28][29], Btla [30], Cd244 [31], and Cd160 [32][33], while coexpressing granzymes and IFN-γ, suggesting the presence of activated, rather than exhausted, T cells. Furthermore, MCTP39 did not appear to play a direct role in enhancing CD8+ T cells activation, supporting the hypothesis that the observed increase in T cell activation was driven by tumor antigens recognition in addition to immunostimulatory cues in the TME that were driven by MCTP39 treatment. Additionally, it is possible that the effects of MCTP39 on T cells may be unique, in that MCTP39 is able to directly diminish T cell exhaustion, although whether this effect is sustained over time is currently unknown and may necessitate blockade of key inhibitory pathways to produce durable T cell responses. In light of this, further efforts to bolster T cell activity in the tumor following MCTP39 may benefit from either combination therapy using checkpoint blockade or through targeting T cell co-stimulatory pathways. Combination therapies usinganti-PD1/PD-L1 could be particularly beneficial, as MCTP39 appears to enhance anti-tumor immunity in vivo, and WHSC1 knockdown in vitro downregulates PD-L1 expression in PCa cancer cells [8]. Since the expression of CD274/PD-L1 by immune cells was maintained following MCTP39 treatment (with the exception of a modest reduction in M1_Committed macrophages expressing CD274/PD-L1 (Figure S3)), combination with anti-PD-L1 therapy could help to reduce the inhibitory signals arising from tumor-infiltrating immune cells and enhance the duration of anti-tumor immunity. Interestingly, recent studies indicate that NK cells appear to benefit from checkpoint blockade therapy, with NK cell responses having a fundamental role in generating maximal anti-tumor immunity [34]. In our system, the pattern of expression of cytotoxic markers in CD8+ T cells and NK cells following treatment indicates that these cell subsets have complementary but different polyfunctional phenotypes, suggesting that a combination of WHSC1 inhibition with checkpoint blockade could optimally activate both cell types, resulting in a potent anti-tumor response. Lastly, because of the increased levels of antigen presentation after MCTP39 treatment [8], we speculate that combination with WHSC1 inhibition could benefit PCa patients who receive vaccines (such as Provenge or Prostvac VF) by preferentially augmenting antigen processing and presentation following vaccination to bolster anti-tumor immunity.
    While a high abundance of intratumoral myeloid cells can be associated with an immunosuppressive TME, macrophages and classical monocytes can promote a sustained inflammatory response and favor T cell homing to the tumor. In our model, inhibition of WHSC1 altered the transcriptional programs of M1 and M2 macrophages, upregulating genes in both antigen processing and presentation and leukocytes migration pathways. These results are in line with the increased frequency of cytotoxic immune cells in the treated group and suggest that myeloid cell reprogramming through MCT39 actively enhances the anti-tumor immune response.
    Due to the coordinated action of chemokine ligands and receptors, immune cells are able to recruit cytotoxic T and NK cells to the target sites [35][36] or, conversely, they can ameliorate an ongoing inflammation process. We surveyed the ligand–receptor pairs for each classified cell type in an attempt to profile the mechanism(s) by which autocrine and paracrine signaling from cytokines and chemokines can rewire the immune behavior in tumors. For example, Nanostring analysis revealed a higher expression of Cd74. CD74, also named MHC II invariant chain [37], acts as chaperone for class II MHC antigen presentation and collaborates with MHC II to present surface antigens to the immune system [38]. In parallel, it is also known to bind to Cxcr4 in monocytes and T cells [39] and to Cxcr2 to promote leukocytes recruitment [40]. Our data indicate increased signaling in macrophages and DCs that promotes CD8+ T cell recruitment via Cxcr2/Cxcr4. These results are consistent with both higher CD8+ T cell infiltration and MHC expression on DCs as measured by flow cytometry, suggesting a potential molecular mechanism by which WHSC1 inhibition alters paracrine signaling in myeloid cells, promoting higher T cell infiltration in the tumor and ultimately establishing an immuno-stimulatory TME. The Ccr5 receptor is uniquely expressed on activated T cells [41][42] and was upregulated in the MCTP39-treated group, in parallel with an upregulation of Ccl5 (a ligand for Ccr5) in DCs, M1, and T_M macrophages. Ccr5 was shown to promote T cell activation in concert with Cxcr4 [42], which can act as receptor for HMGB1 [43], Cxcl12 [44][45], and Cd74 [46]. While computational predictions suggest that complementary pro-inflammatory signals converge to establish a potent anti-tumor immune response, further experimental validation of the changes in cytokine and chemokine levels in each cell type would allow for a more precise interpretation of MCTP39 activity in the TME. The use of multiple prostate cancer models paired with toxicity analyses would further help to expand our current understanding of the safety and clinical applicability of the pharmacological inhibition of WHSC1, thus allowing for these findings to be translated as a clinically actionable treatment approach.
    In conclusion, we present a detailed study that addresses the role of WHSC1 in altering anti-tumor cytotoxicity by rewiring the chemokine and cytokine signaling governing the communication between myeloid and lymphoid cells that infiltrate tumors. Due to the vast array of pro-tumorigenic functions shared by WHSC1 across cancer types [1][2][3][4][5][6][7], future studies that extend this approach to other tumor indications will reveal whether WHSC1 has a pan- or multi-cancer immuno-modulatory role. The downstream consequences of these findings have direct therapeutic implications, where cancer patients can be stratified based on WHSC1 expression to identify those that would benefit from WHSC1 inhibition as a complementary approach to immunotherapy.

    The entry is from 10.3390/ijms22168742

    References

    1. Li, N.; Xue, W.; Yuan, H.; Dong, B.; Ding, Y.; Liu, Y.; Jiang, M.; Kan, S.; Sun, T.; Ren, J.; et al. AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis. J. Clin. Investig. 2017, 127, 1284–1302.
    2. Garcia-Carpizo, V.; Sarmentero, J.; Han, B.; Grana, O.; Ruiz-Llorente, S.; Pisano, D.G.; Serrano, M.; Brooks, H.B.; Campbell, R.M.; Barrero, M.J. NSD2 contributes to oncogenic RAS-driven transcription in lung cancer cells through long-range epigenetic activation. Sci. Rep. 2016, 6, 32952.
    3. Zhu, L.; Yu, C.L.; Zheng, Y. NSD2 inhibition suppresses metastasis in cervical cancer by promoting TGF-beta/TGF-betaRI/SMADs signaling. Biochem. Biophys. Res. Commun. 2019, 519, 489–496.
    4. Aytes, A.; Giacobbe, A.; Mitrofanova, A.; Ruggero, K.; Cyrta, J.; Arriaga, J.; Palomero, L.; Farran-Matas, S.; Rubin, M.A.; Shen, M.M.; et al. NSD2 is a conserved driver of metastatic prostate cancer progression. Nat. Commun. 2018, 9, 5201.
    5. Kuo, A.J.; Cheung, P.; Chen, K.; Zee, B.M.; Kioi, M.; Lauring, J.; Xi, Y.; Park, B.H.; Shi, X.; Garcia, B.A.; et al. NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. Mol. Cell 2011, 44, 609–620.
    6. Dai, J.; Jiang, L.; Qiu, L.; Shao, Y.; Shi, P.; Li, J. WHSC1 Promotes Cell Proliferation, Migration, and Invasion in Hepatocellular Carcinoma by Activating mTORC1 Signaling. Onco Targets Ther. 2020, 13, 7033–7044.
    7. Zhang, J.; Lu, J.; Chen, Y.; Li, H.; Lin, L. WHSC1 promotes wnt/beta-catenin signaling in a FoxM1-dependent manner facilitating proliferation, invasion and epithelial-mesenchymal transition in breast cancer. J. Recept. Signal. Transduct. Res. 2020, 40, 410–418.
    8. Want, M.Y.; Tsuji, T.; Singh, P.K.; Thorne, J.L.; Matsuzaki, J.; Karasik, E.; Gillard, B.; Cortes Gomez, E.; Koya, R.C.; Lugade, A.; et al. WHSC1/NSD2 regulates immune infiltration in prostate cancer. J. Immunother. Cancer 2021, 9, e001374.
    9. Gubin, M.M.; Esaulova, E.; Ward, J.P.; Malkova, O.N.; Runci, D.; Wong, P.; Noguchi, T.; Arthur, C.D.; Meng, W.; Alspach, E.; et al. High-Dimensional Analysis Delineates Myeloid and Lymphoid Compartment Remodeling during Successful Immune-Checkpoint Cancer Therapy. Cell 2018, 175, 1014–1030 e19.
    10. Dudzinski, S.O.; Cameron, B.D.; Wang, J.; Rathmell, J.C.; Giorgio, T.D.; Kirschner, A.N. Combination immunotherapy and radiotherapy causes an abscopal treatment response in a mouse model of castration resistant prostate cancer. J. Immunother. Cancer 2019, 7, 218.
    11. Gu, S.S.; Wang, X.; Hu, X.; Jiang, P.; Li, Z.; Traugh, N.; Bu, X.; Tang, Q.; Wang, C.; Zeng, Z.; et al. Clonal tracing reveals diverse patterns of response to immune checkpoint blockade. Genome Biol. 2020, 21, 263.
    12. Sade-Feldman, M.; Yizhak, K.; Bjorgaard, S.L.; Ray, J.P.; de Boer, C.G.; Jenkins, R.W.; Lieb, D.J.; Chen, J.H.; Frederick, D.T.; Barzily-Rokni, M.; et al. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell 2018, 175, 998–1013 e20.
    13. Buque, A.; Bloy, N.; Perez-Lanzon, M.; Iribarren, K.; Humeau, J.; Pol, J.G.; Levesque, S.; Mondragon, L.; Yamazaki, T.; Sato, A.; et al. Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer. Nat. Commun. 2020, 11, 3819.
    14. Olson, B.M.; Gamat, M.; Seliski, J.; Sawicki, T.; Jeffery, J.; Ellis, L.; Drake, C.G.; Weichert, J.; McNeel, D.G. Prostate Cancer Cells Express More Androgen Receptor (AR) Following Androgen Deprivation, Improving Recognition by AR-Specific T Cells. Cancer Immunol. Res. 2017, 5, 1074–1085.
    15. Want, M.Y.; Konstorum, A.; Huang, R.Y.; Jain, V.; Matsueda, S.; Tsuji, T.; Lugade, A.; Odunsi, K.; Koya, R.; Battaglia, S. Neoantigens retention in patient derived xenograft models mediates autologous T cells activation in ovarian cancer. Oncoimmunology 2019, 8, e1586042.
    16. Foster, B.A.; Gingrich, J.R.; Kwon, E.D.; Madias, C.; Greenberg, N.M. Characterization of prostatic epithelial cell lines derived from transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Cancer Res. 1997, 57, 3325–3330.
    17. Chen, S.; Zhu, G.; Yang, Y.; Wang, F.; Xiao, Y.T.; Zhang, N.; Bian, X.; Zhu, Y.; Yu, Y.; Liu, F.; et al. Single-cell analysis reveals transcriptomic remodellings in distinct cell types that contribute to human prostate cancer progression. Nat. Cell Biol. 2021, 23, 87–98.
    18. Rohrle, N.; Knott, M.M.L.; Anz, D. CCL22 Signaling in the Tumor Environment. Adv. Exp. Med. Biol 2020, 1231, 79–96.
    19. Rapp, M.; Wintergerst, M.W.M.; Kunz, W.G.; Vetter, V.K.; Knott, M.M.L.; Lisowski, D.; Haubner, S.; Moder, S.; Thaler, R.; Eiber, S.; et al. CCL22 controls immunity by promoting regulatory T cell communication with dendritic cells in lymph nodes. J. Exp. Med. 2019, 216, 1170–1181.
    20. Hauser, M.A.; Legler, D.F. Common and biased signaling pathways of the chemokine receptor CCR7 elicited by its ligands CCL19 and CCL21 in leukocytes. J. Leukoc. Biol. 2016, 99, 869–882.
    21. Xiong, Y.; Huang, F.; Li, X.; Chen, Z.; Feng, D.; Jiang, H.; Chen, W.; Zhang, X. CCL21/CCR7 interaction promotes cellular migration and invasion via modulation of the MEK/ERK1/2 signaling pathway and correlates with lymphatic metastatic spread and poor prognosis in urinary bladder cancer. Int. J. Oncol. 2017, 51, 75–90.
    22. Kobayashi, D.; Endo, M.; Ochi, H.; Hojo, H.; Miyasaka, M.; Hayasaka, H. Regulation of CCR7-dependent cell migration through CCR7 homodimer formation. Sci. Rep. 2017, 7, 8536.
    23. Kazanietz, M.G.; Durando, M.; Cooke, M. CXCL13 and Its Receptor CXCR5 in Cancer: Inflammation, Immune Response, and Beyond. Front. Endocrinol. (Lausanne) 2019, 10, 471.
    24. Ager, C.R.; Reilley, M.J.; Nicholas, C.; Bartkowiak, T.; Jaiswal, A.R.; Curran, M.A. Intratumoral STING Activation with T-cell Checkpoint Modulation Generates Systemic Antitumor Immunity. Cancer Immunol. Res. 2017, 5, 676–684.
    25. Philippou, Y.; Sjoberg, H.T.; Murphy, E.; Alyacoubi, S.; Jones, K.I.; Gordon-Weeks, A.N.; Phyu, S.; Parkes, E.E.; Gillies McKenna, W.; Lamb, A.D.; et al. Impacts of combining anti-PD-L1 immunotherapy and radiotherapy on the tumour immune microenvironment in a murine prostate cancer model. Br. J. Cancer 2020, 123, 1089–1100.
    26. Jahchan, N.S.; Mujal, A.M.; Pollack, J.L.; Binnewies, M.; Sriram, V.; Reyno, L.; Krummel, M.F. Tuning the Tumor Myeloid Microenvironment to Fight Cancer. Front. Immunol. 2019, 10, 1611.
    27. Yang, Z.Z.; Kim, H.J.; Villasboas, J.C.; Chen, Y.P.; Price-Troska, T.; Jalali, S.; Wilson, M.; Novak, A.J.; Ansell, S.M. Expression of LAG-3 defines exhaustion of intratumoral PD-1(+) T cells and correlates with poor outcome in follicular lymphoma. Oncotarget 2017, 8, 61425–61439.
    28. Tian, X.; Zhang, A.; Qiu, C.; Wang, W.; Yang, Y.; Qiu, C.; Liu, A.; Zhu, L.; Yuan, S.; Hu, H.; et al. The upregulation of LAG-3 on T cells defines a subpopulation with functional exhaustion and correlates with disease progression in HIV-infected subjects. J. Immunol 2015, 194, 3873–3882.
    29. Blackburn, S.D.; Shin, H.; Haining, W.N.; Zou, T.; Workman, C.J.; Polley, A.; Betts, M.R.; Freeman, G.J.; Vignali, D.A.; Wherry, E.J. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 2009, 10, 29–37.
    30. Derre, L.; Rivals, J.P.; Jandus, C.; Pastor, S.; Rimoldi, D.; Romero, P.; Michielin, O.; Olive, D.; Speiser, D.E. BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination. J. Clin. Invest. 2010, 120, 157–167.
    31. Laurie, S.J.; Liu, D.; Wagener, M.E.; Stark, P.C.; Terhorst, C.; Ford, M.L. 2B4 Mediates Inhibition of CD8(+) T Cell Responses via Attenuation of Glycolysis and Cell Division. J. Immunol. 2018, 201, 1536–1548.
    32. Vigano, S.; Banga, R.; Bellanger, F.; Pellaton, C.; Farina, A.; Comte, D.; Harari, A.; Perreau, M. CD160-associated CD8 T-cell functional impairment is independent of PD-1 expression. PLoS Pathog. 2014, 10, e1004380.
    33. Chibueze, C.E.; Yoshimitsu, M.; Arima, N. CD160 expression defines a uniquely exhausted subset of T lymphocytes in HTLV-1 infection. Biochem. Biophys. Res. Commun. 2014, 453, 379–384.
    34. Hsu, J.; Hodgins, J.J.; Marathe, M.; Nicolai, C.J.; Bourgeois-Daigneault, M.C.; Trevino, T.N.; Azimi, C.S.; Scheer, A.K.; Randolph, H.E.; Thompson, T.W.; et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Invest. 2018, 128, 4654–4668.
    35. Baggiolini, M. Chemokines in pathology and medicine. J. Intern. Med. 2001, 250, 91–104.
    36. Gao, J.Q.; Okada, N.; Mayumi, T.; Nakagawa, S. Immune cell recruitment and cell-based system for cancer therapy. Pharm. Res. 2008, 25, 752–768.
    37. Leng, L.; Metz, C.N.; Fang, Y.; Xu, J.; Donnelly, S.; Baugh, J.; Delohery, T.; Chen, Y.; Mitchell, R.A.; Bucala, R. MIF signal transduction initiated by binding to CD74. J. Exp. Med. 2003, 197, 1467–1476.
    38. Karakikes, I.; Morrison, I.E.; O’Toole, P.; Metodieva, G.; Navarrete, C.V.; Gomez, J.; Miranda-Sayago, J.M.; Cherry, R.J.; Metodiev, M.; Fernandez, N. Interaction of HLA-DR and CD74 at the cell surface of antigen-presenting cells by single particle image analysis. FASEB J. 2012, 26, 4886–4896.
    39. Schwartz, V.; Lue, H.; Kraemer, S.; Korbiel, J.; Krohn, R.; Ohl, K.; Bucala, R.; Weber, C.; Bernhagen, J. A functional heteromeric MIF receptor formed by CD74 and CXCR4. FEBS Lett. 2009, 583, 2749–2757.
    40. Bernhagen, J.; Krohn, R.; Lue, H.; Gregory, J.L.; Zernecke, A.; Koenen, R.R.; Dewor, M.; Georgiev, I.; Schober, A.; Leng, L.; et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat. Med. 2007, 13, 587–596.
    41. Wang, X.; Russell-Lodrigue, K.E.; Ratterree, M.S.; Veazey, R.S.; Xu, H. Chemokine receptor CCR5 correlates with functional CD8(+) T cells in SIV-infected macaques and the potential effects of maraviroc on T-cell activation. FASEB J. 2019, 33, 8905–8912.
    42. Contento, R.L.; Molon, B.; Boularan, C.; Pozzan, T.; Manes, S.; Marullo, S.; Viola, A. CXCR4-CCR5: A couple modulating T cell functions. Proc. Natl. Acad. Sci. USA 2008, 105, 10101–10106.
    43. Li, G.; Liang, X.; Lotze, M.T. HMGB1: The Central Cytokine for All Lymphoid Cells. Front. Immunol. 2013, 4, 68.
    44. Bleul, C.C.; Farzan, M.; Choe, H.; Parolin, C.; Clark-Lewis, I.; Sodroski, J.; Springer, T.A. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 1996, 382, 829–833.
    45. Salcedo, R.; Wasserman, K.; Young, H.A.; Grimm, M.C.; Howard, O.M.; Anver, M.R.; Kleinman, H.K.; Murphy, W.J.; Oppenheim, J.J. Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: In vivo neovascularization induced by stromal-derived factor-1alpha. Am. J. Pathol. 1999, 154, 1125–1135.
    46. Hughes, C.E.; Nibbs, R.J.B. A guide to chemokines and their receptors. FEBS J. 2018, 285, 2944–2971.
    More