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Wei, Z.; Zhang, Y. CD4+ T Cells in Immunotherapy. Encyclopedia. Available online: https://encyclopedia.pub/entry/23653 (accessed on 22 December 2025).
Wei Z, Zhang Y. CD4+ T Cells in Immunotherapy. Encyclopedia. Available at: https://encyclopedia.pub/entry/23653. Accessed December 22, 2025.
Wei, Zhanqi, Yuewei Zhang. "CD4+ T Cells in Immunotherapy" Encyclopedia, https://encyclopedia.pub/entry/23653 (accessed December 22, 2025).
Wei, Z., & Zhang, Y. (2022, June 01). CD4+ T Cells in Immunotherapy. In Encyclopedia. https://encyclopedia.pub/entry/23653
Wei, Zhanqi and Yuewei Zhang. "CD4+ T Cells in Immunotherapy." Encyclopedia. Web. 01 June, 2022.
CD4+ T Cells in Immunotherapy
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This entry is adapted from the peer-reviewed paper 10.3390/cells11111758

Immunotherapy research has often focused on CD8+ T cells because of their ability to eliminate tumor cells. However, CD4+ T cells have attracted attention in the field because they are not only crucial for promoting CD8+ T cell functions, preventing CD8+ T cell depletion or inducing CD8+ T cell memory, but also able to directly or indirectly kill tumor cells.

immunotherapy hyperprogressive disease immune cells

1. Regulatory T (Treg) Cells

In addition to effector cells, the T lymphocyte family includes an immunomodulatory subgroup called Treg cells, whose role is to negatively regulate other immune cells, prevent the overactivation of the immune response, and play a role in a wide range of diseases, such as allergies, chronic infections, and parasitic infections [1]. However, the presence of Treg cells is disadvantageous to hosts with tumors because they limit an effective antitumor immune response. Kamada et al. [2] reported that the proportions of effector regulatory T (eTreg) cells/CD8 T cells, Ki67 Treg cells/Ki67CD8 T cells, and Ki67 Treg cells decreased significantly in non-HPD patients after treatment with anti-PD-1 antibodies, while these proportions in HPD patients remained stable or even increased slightly. This finding suggested that if the number of CD8 T cells is insufficient to overcome Treg cells, the possibility of HPD development is greatly increased. Furthermore, Treg cells have also been shown to express immune checkpoints, such as PD-1; thus, Treg cells can also be targeted by anti-PD-1 agents [3]. Researchers have observed that knocking out PD-1 in Treg cells or blocking PD-1 with monoclonal antibodies (mAbs) caused Treg cells to gain a stronger proliferative ability and a stronger immunosuppression ability, thus leading to a stronger ability to promote tumor growth. This finding suggested that PD-1 Treg cells play a key role in anti-PD-1 treatment-mediated HPD in advanced gastric cancer. In addition, Ratner et al. [4][5] demonstrated that nivolumab led to rapid progression in patients with adult T-cell leukemia/lymphoma (ATLL). They identified a novel relationship between tumor-resident Tregs and ATLL cells and revealed the tumor suppressive effect of PD-1 in ATLL.+++++++
Furthermore, in Treg cells treated with PD-1 blockade, the expression of immune checkpoints is upregulated, and the immunosuppressive function is enhanced. Thus, the antitumor immunity of some patients after anti-PD-1 treatment is not enhanced but greatly weakened, which leads to the occurrence of HPD. Interestingly, CTLA-4 was found to be strongly expressed in Treg cells [6]. Anti-CTLA-4 treatment increased the presence of Ki67 Treg cells [2]. Furthermore, the combination of anti-CTLA-4 antibodies and anti-PD-1 antibodies was associated with a lower incidence of HPD than other ICI combinations, and CTLA-4, OX-40, or CCR4-targeted therapy might be a strategy for preventing HPD through Treg cell consumption [7]. In addition, selective PD-1/PD-L1 inhibition may lead to tumor immune evasion and accelerate tumor growth by increasing the number of Treg cells infiltrating and circulating in the tumor [8].+

2. Other Subsets of CD4 T Cells+

CD4CD28+− T cells are a cell subpopulation with unique biological effects that frequently appear in some autoimmune diseases [9]. Due to their lack of CD28, which is necessary for a cell-specific immune response and the most important costimulatory molecule on the T-cell surface, these unique cells not only have abnormal immune function but also have the characteristics of autoreactivity, massive expansion, and a long lifespan [10]. Arasanz et al. [11] found that CD4CD28+− T cells in the peripheral blood of lung cancer patients with HPD were amplified after PD-1 treatment, and high tumor growth dynamics scores were associated with the presence of CD4CD28+− T-cell subsets in patients with HPD.
In addition, Zappasodi et al. [12] observed in melanoma mice that a subset of CD4Foxp3+−PD-1high T cells can perform immunosuppressive functions similar to those of Treg cells, but their RNA expression levels may be more similar to those of follicular helper T (Tfh) cells. Interestingly, while anti-PD-1 treatment reduced the numbers of these cells, anti-CTLA4 treatment increased their intratumoral abundance. This result suggests that this cell subpopulation could also respond to ICB, proliferate under anti-CTLA-4 treatment, and acquire negative regulatory immune properties, which might contribute to the development of HPD.

3. Exhausted CD4+ T Cells

Another potential mechanism of HPD is the correlation between exhausted CD4+ T cells and anti-PD-1 treatment. The current understanding of CD4+ T cell exhaustion is obviously insufficient. However, the negative effects of CD4+ T cell exhaustion on proliferation, cytokine production, B-cell help, and CD8+ effector functions have been reported. Furthermore, exhausted CD4+ T cells upregulate immune-regulatory proteins, such as TIM3 and PD-1, paralleling phenotypes observed in exhausted CD8+ T cells [13]. Unlike non-HPD patients, HPD patients showed abnormal dilation of peripheral exhausted memory CD4+ T cells after the initial administration of anti-PD-1/PD-L1 antibodies [14]. Arasanz et al. [14] monitored peripheral blood mononuclear cells (PBMCs) in NSCLC patients treated with anti-PD-1/PD-L1 antibodies, and peripheral exhausted CD4+ T-cell proliferation was observed in patients with HPD. They proposed that the rapid expansion of peripheral CD28-CD4+ T cells is an early distinguishing feature of ICIs-induced HPD in NSCLC. Although the role of exhausted CD4+ T cells is not fully understood, these studies provide important evidence that these cells might also contribute to the progression of HPD.

4. IFN-γ

While IFN-γ is considered to be a key factor in antitumor immunity [15][16], Xiao et al. [17] demonstrated that IFN-γ could promote immune escape and papilloma development by enhancing a Th17-associated inflammatory reaction. Thus, IFN-γ can promote either antitumor immunity or immune escape according to the pathological background and the level of selective stress [18]. Sakai et al. [19] reported that in a mouse model of Mycobacterium tuberculosis infection, PD-1- led to the extensive penetration of CD4+ T cells into the lung parenchyma and the production of large amounts of IFN-γ, causing rapid disease progression, compared with that observed in wild-type mice. In addition, mutations in genes encoding IFN-γ signaling pathway components, such as IFN-γ receptor and JAK1/2, have been identified as potential mechanisms of resistance against anti-PD-1/PD-L1 and anti-CTLA-4 antibodies [16][20]. Champiat et al. [21] noted that T-cell behavior in the TME under ICB may be affected by mutations that affect the IFN-γ signaling pathway, particularly mutations in JAK1/2. JAK1/2 mutations have been proven to be associated with primary resistance to ICIs [22]. In addition, it has been reported that IFN-γ-induced interferon regulatory factor 8 (IRF-8) binds to its promoter and induces MDM2 overexpression [23][24]. MDM2 is a protein involved in p53 degradation and inhibition, and its amplification is often observed in HPD patients [23].

References

  1. Togashi, Y.; Shitara, K.; Nishikawa, H. Regulatory T cells in cancer immunosuppression—Implications for anticancer therapy. Nat. Rev. Clin. Oncol. 2019, 16, 356–371.
  2. Kamada, T.; Togashi, Y.; Tay, C.; Ha, D.; Sasaki, A.; Nakamura, Y.; Sato, E.; Fukuoka, S.; Tada, Y.; Tanaka, A.; et al. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc. Natl. Acad. Sci. USA 2019, 116, 9999–10008.
  3. Cai, J.J.; Wang, D.S.; Zhang, G.Y.; Guo, X.L. The Role Of PD-1/PD-L1 Axis In Treg Development And Function: Implica-tions For Cancer Immunotherapy. Oncotargets Ther. 2019, 12, 8437–8445.
  4. Ratner, L.; Waldmann, T.A.; Janakiram, M.; Brammer, J.E. Rapid Progression of Adult T-Cell Leukemia–Lymphoma after PD-1 Inhibitor Therapy. N. Engl. J. Med. 2018, 378, 1947–1948.
  5. Rauch, D.A.; Conlon, K.C.; Janakiram, M.; Brammer, J.E.; Harding, J.C.; Ye, B.H.; Zang, X.; Ren, X.; Olson, S.; Cheng, X.; et al. Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade. Blood 2019, 134, 1406–1414.
  6. Simpson, T.R.; Li, F.; Montalvo-Ortiz, W.; Sepulveda, M.A.; Bergerhoff, K.; Arce, F.; Roddie, C.; Henry, J.Y.; Yagita, H.; Wolchok, J.D.; et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma. J. Exp. Med. 2013, 210, 1695–1710.
  7. Ji, Z.; Peng, Z.; Gong, J.; Zhang, X.; Li, J.; Lu, M.; Lu, Z.; Shen, L. Hyperprogression after immunotherapy in patients with malignant tumors of digestive system. BMC Cancer 2019, 19, 1–9.
  8. Champiat, S.; Ferrara, R.; Massard, C.; Besse, B.; Marabelle, A.; Soria, J.-C.; Ferté, C. Hyperprogressive disease: Recognizing a novel pattern to improve patient management. Nat. Rev. Clin. Oncol. 2018, 15, 748–762.
  9. Lee, G.H.; Lee, W.-W. Unusual CD4+CD28−T Cells and Their Pathogenic Role in Chronic Inflammatory Disorders. Immune Netw. 2016, 16, 322–329.
  10. Maly, K.; Schirmer, M. The Story of CD4+ CD28− T Cells Revisited: Solved or Still Ongoing? J. Immunol. Res. 2015, 2015, 348746.
  11. Arasanz, H.; Zuazo, M.; Bocanegra, A.; Gato, M.; Martinez-Aguillo, M.; Morilla, I.; Fernandez, G.; Hernandez, B.; Lopez, P.; Alberdi, N.; et al. Early Detection of Hyperprogressive Dis-ease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics. Cancers 2020, 12, 344.
  12. Zappasodi, R.; Budhu, S.; Hellmann, M.D.; Postow, M.A.; Senbabaoglu, Y.; Manne, S.; Gasmi, B.; Liu, C.L.; Zhong, H.; Li, Y.Y.; et al. Non-conventional Inhibi-tory CD4(+)Foxp3(-)PD-1(hi) T Cells as a Biomarker of Immune Checkpoint Blockade Activity. Cancer Cell 2018, 33, 1017–1032.e7.
  13. Miggelbrink, A.M.; Jackson, J.D.; Lorrey, S.J.; Srinivasan, E.S.; Waibl-Polania, J.; Wilkinson, D.S.; Fecci, P.E. CD4 T-Cell Exhaustion: Does It Exist and What Are Its Roles in Cancer? Clin. Cancer Res. 2021, 27, 5742–5752.
  14. Arasanz, H.; Zuazo, M.; Bocanegra, A.; Gato, M.; Martinez-Aguillo, M.; Morilla, I.; Fernandez, G.; Hernandez, B.; Lopez, P.; Alberdi, N.; et al. Early Detection of Hyperprogressive Dis-ease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics. Cancers 2020, 12, 344.
  15. Martini, M.; Testi, M.G.; Pasetto, M.; Picchio, M.C.; Innamorati, G.; Mazzocco, M.; Ugel, S.; Cingarlini, S.; Bronte, V.; Zanovello, P.; et al. IFN-gamma-mediated upmodulation of MHC class I expression activates tumor-specific immune response in a mouse model of prostate cancer. Vaccine 2010, 28, 3548–3557.
  16. Zimmerman, M.; Yang, D.F.; Hu, X.L.; Liu, F.Y.; Singh, N.; Browning, D.; Ganapathy, V.; Chandler, P.; Choubey, D.; Abrams, S.I.; et al. IFN-gamma Upregulates Survivin and Ifi202 Expression to Induce Survival and Proliferation of Tumor-Specific T Cells. PLoS ONE 2010, 5.
  17. Xiao, M.J.; Wang, C.H.; Zhang, J.H.; Li, Z.G.; Zhao, X.Q.; Qin, Z.H. IFN gamma Promotes Papilloma Development by Up-regulating Th17-Associated Inflammation. Cancer Res. 2009, 69, 2010–2017.
  18. O’Garra, A.; Barrat, F.J.; Castro, G.; Vicari, A.; Hawrylowicz, C. Strategies for use of IL-10 or its antagonists in human disease. Immunol. Rev. 2008, 223, 114–131.
  19. Sakai, S.; Kauffman, K.D.; Sallin, M.A.; Sharpe, A.H.; Young, H.A.; Ganusov, V.V.; Barber, D.L. CD4 T Cell-Derived IFN-gamma Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Re-pressed by PD-1 to Prevent Lethal Disease. PLoS Pathog. 2016, 12, e1005667.
  20. Rosenkranz, D.; Weyer, S.; Tolosa, E.; Gaenslen, A.; Berg, D.; Leyhe, T.; Gasser, T.; Stoltze, L. Higher frequency of regulatory T suppressive activity cells in the elderly and increased in neurodegeneration. J. Neuroimmunol. 2007, 188, 117–127.
  21. Cimino-Mathews, A.; Foote, J.B.; Emens, L.A. Immune Targeting in Breast Cancer. Oncology 2015, 29, 375–385.
  22. Shin, D.S.; Zaretsky, J.M.; Escuin-Ordinas, H.; Garcia-Diaz, A.; Hu-Lieskovan, S.; Kalbasi, A.; Grasso, C.S.; Hugo, W.; Sandoval, S.; Torrejon, D.Y.; et al. Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations. Cancer Discov. 2017, 7, 188–201.
  23. Kato, S.; Goodman, A.; Walavalkar, V.; Barkauskas, D.A.; Sharabi, A.; Kurzrock, R. Hyperprogressors after Immunothera-py: Analysis of Genomic Alterations Associated with Accelerated Growth Rate. Clin. Cancer Res. 2017, 23, 4242–4250.
  24. Zhou, J.X.; Lee, C.H.; Qi, C.F.; Wang, H.; Naghashfar, Z.; Abbasi, S.; Morse, H.C. IFN Regulatory Factor 8 Regulates MDM2 in Germinal Center B Cells. J. Immunol. 2009, 183, 3188–3194.
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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Zhanqi Wei , Yuewei Zhang
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Update Date: 16 Jun 2022
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