Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Irene Gullo
 + 1481 word(s) 1481 2021-09-16 08:00:05 |
2 update layout and reference
Rita Xu
-192 word(s) 1289 2021-10-08 04:08:18 | |
3 change type
Rita Xu
-192 word(s) 1289 2021-10-08 04:08:47 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Gullo, I. Adaptive Immune Landscape of Colorectal Adenoma-Carcinoma Sequence. Encyclopedia. Available online: https://encyclopedia.pub/entry/14853 (accessed on 26 April 2024).
Gullo I. Adaptive Immune Landscape of Colorectal Adenoma-Carcinoma Sequence. Encyclopedia. Available at: https://encyclopedia.pub/entry/14853. Accessed April 26, 2024.
Gullo, Irene. "Adaptive Immune Landscape of Colorectal Adenoma-Carcinoma Sequence" Encyclopedia, https://encyclopedia.pub/entry/14853 (accessed April 26, 2024).
Gullo, I. (2021, October 06). Adaptive Immune Landscape of Colorectal Adenoma-Carcinoma Sequence. In Encyclopedia. https://encyclopedia.pub/entry/14853
Gullo, Irene. "Adaptive Immune Landscape of Colorectal Adenoma-Carcinoma Sequence." Encyclopedia. Web. 06 October, 2021.
Adaptive Immune Landscape of Colorectal Adenoma-Carcinoma Sequence
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ijms22189791

The tumor immune microenvironment exerts a pivotal influence in tumor initiation and progression.

colorectal adenoma colorectal adenocarcinoma familial adenomatous polyposis APC germline alterations

1. Introduction

The etiopathogenesis of most colorectal carcinomas (CRC) follows the conventional adenoma–carcinoma sequence (ACS), in which colorectal adenomas with low-grade dysplasia (LGD) and/or high-grade dysplasia (HGD) evolve to invasive adenocarcinoma (ADC), through a stepwise accumulation of genetic and epigenetic alterations. The earliest events in colorectal tumorigenesis involve alterations of the WNT signaling pathway, most frequently through somatic mutation of the adenomatous polyposis coli (APC) gene [1][2][3]. Germline mutations in the APC gene are the genetic cause of familial adenomatous polyposis (FAP), an autosomal dominant syndrome characterized by numerous adenomatous lesions in the colorectum, and early onset CRC.
The tumor immune microenvironment has a crucial role in the development and progression of colorectal precursor and invasive lesions [4]. Moreover, the amount, type, and location of tumor-infiltrating lymphocytes have been shown to have prognostic value in CRC patients [5][6][7]. With the widespread use of targeted immunotherapy in solid tumors, including CRC [8], there is a growing research interest in exploring the role of the tumor immune microenvironment also as a predictive biomarker. Currently, monoclonal antibodies against immune checkpoints, e.g., CTLA4, PD-1, and PD-L1, have been approved in microsatellite instability-high (MSI-H) CRCs and microsatellite-stable (MSS) tumors with high tumor mutation burden (TMB) [9][10], reflecting the immunogenicity of these tumor subtypes [11].
In the current body of literature, great attention has been given to the immune landscape of invasive ADC, whereas few studies have compared the tumor immune microenvironment of pre-invasive and malignant lesions, with contradictory findings [4][12][13][14][15][16]. Some studies have demonstrated a lower expression of Th1 cytokines, a shift to a Th2 cytokine profile [4][15], and a decrease in cytotoxic CD8+ T cell counts along ACS [17][18], whereas others have suggested an increase in the density of T lymphocytes, regulatory T cells, and macrophages during tumor progression [4][14][16]. Likewise, little information is available regarding the comparison of human colorectal neoplastic lesions arising from a sporadic or hereditary background, since most studies on hereditary cancer have used mouse models, especially APCmin mice [19]. Furthermore, most of the studies in human colorectal cancer focused on MSI tumors. A study by Liu, G. et al. showed that the number of CD3+, CD8+, CD4+ and FoxP3+ cells in the invasive margin or tumor stroma is higher in Lynch syndrome cases than in sporadic cases [20]. Therefore, an in-depth characterization of the human tumor immune landscape and its evolution along the colorectal ACS is needed, especially for MSS colorectal cancer.

2. Tumor Infiltration with Immune Cells Decreases throughout the Colorectal ACS

To investigate the evolution of the tumor immune microenvironment along the colorectal ACS, we analyzed the density and quality of the immune infiltration in adenomatous lesions with LGD, with HGD, and in invasive ADCs. By immunohistochemistry and counting representative areas, we analyzed and normalized the density of the overall population of CD3+ T lymphocytes per mm2, as well as the specific populations of CD4+ helper T cells, cytotoxic CD8+ T lymphocytes, Foxp3+ regulatory T cells, and CD57+ T lymphocytes/natural killer (NK) cells.
We observed an overall decrease in tumor-infiltrating immune cells along the colorectal ACS in both sporadic and hereditary FAP-related cohorts (Figure 1). Adenomatous lesions with LGD harbored higher counts of CD3+, CD4+, CD8+, and CD57+ immune cells when compared with adenomatous lesions with HGD and invasive ADCs, in both sporadic and hereditary FAP-related lesions. These findings were more pronounced in sporadic lesions, with p-values < 0.001 when adenomatous lesions with LGD were compared with ADCs. Although the density of Foxp3+ regulatory T cells followed the same decrease pattern in the sporadic context, this was not observed in lesions from FAP patients. As the spatial distribution of immune cell types within the tumors could be relevant in the interpretation of our results, we studied the immune cell density separately at the center and at the front of invasive ADCs. No differences were found between the two locations (data not shown) and the results on immune cell counts were considered as a whole.
Ijms 22 09791 g002 550
Figure 1. Counts of immune cells along the colorectal adenoma-carcinoma sequence in sporadic (A) and hereditary Familial Adenomatous Polyposis (FAP)-related (B) lesions. LGD, low-grade dysplasia; HGD, high-grade dysplasia; ADC, invasive adenocarcinoma; * = p < 0.05; ** = p < 0.01; *** = p < 0.001; **** = p < 0.0001.
To assess whether the tumor immune microenvironment could vary depending on the hereditary or sporadic background of the neoplastic lesions, we investigated the immune landscape between the two cohorts for LGD, HGD, and invasive ADC lesions (Figure 2).
Ijms 22 09791 g003 550
Figure 2. Comparison of immune cell counts between sporadic and hereditary Familial Adenomatous Polyposis (FAP)-related lesions in adenomatous lesions with low-grade dysplasia (A), adenomatous lesions with high-grade dysplasia (B), and invasive adenocarcinoma (C). * = p < 0.05; **** = p < 0.0001.
We found that adenomas with LGD from FAP patients displayed a marginal increase in CD8+ T cells (p < 0.05) and a significantly lower density of Foxp3+ (p < 0.0001) T cells when compared with sporadic adenomas with LGD. No differences were observed for the remaining adaptive immune cell populations, or subgroups of sporadic and hereditary lesions.
In conclusion, our findings suggest that colorectal neoplastic lesions trigger a host immune response, but become immunologically colder throughout the colorectal ACS. This was observed for both sporadic and hereditary lesions, although it was more pronounced in the former. In that regard, we would like to stress the higher density of Foxp3+ regulatory T cells in sporadic versus hereditary LGD lesions, suggesting that the host has a higher baseline immunological tolerance towards hereditary lesions.

3. TMB and MHC-I Expression Increase along the Colorectal ACS

We hypothesized that the decrease in immune cells counts along the ACS could be partially explained by the progressive loss of immunogenicity [21][22]. To explore this hypothesis, we evaluated TMB and the expression of the major histocompatibility complex class I (MHC-I) protein in tumor cells as surrogates to tumor antigenicity, and to the ability of tumor cells to present neoantigens to the immune system, respectively.
We found that TMB increased throughout the ACS in sporadic cases (Figure 3A), from the median value of 2.76 mutation/mega base pair (mut/Mbp) in LGD lesions to 15.76 mut/Mbp in ADC cases (p < 0.05). In contrast, this trend was not observed in hereditary FAP-related lesions (Figure 3B), where the average number of mut/Mbp remained constant along the ACS, despite the presence of some outlier samples. Likewise, we found that MHC-I expression in neoplastic cells progressively increased throughout the ACS in both FAP-related (p = 0.033) and sporadic (p = 0.025) lesions (Figure 4). MHC-I was expressed at the cell membrane, as well as in the cytoplasm of neoplastic cells (Figure 5).
Ijms 22 09791 g004 550
Figure 3. TMB analysis along the colorectal adenoma-carcinoma in sporadic (A) and hereditary Familial Adenomatous Polyposis (FAP)-related (B) lesions. * = p < 0.05. LGD, low-grade dysplasia (circles); HGD, high-grade dysplasia (squares); ADC, invasive adenocarcinoma (triangles); * = p < 0.05.
Ijms 22 09791 g005 550
Figure 4. Percentage of cases in which MHC-I in tumor cells is >25% (score 1) along the colorectal adenoma-carcinoma sequence, in sporadic (A) and hereditary Familial Adenomatous Polyposis (FAP)-related (B) lesions. LGD, low-grade dysplasia; HGD, high-grade dysplasia; ADC, invasive adenocarcinoma.
Ijms 22 09791 g006 550
Figure 5. MHC-I and PD-L1 expression along the colorectal adenoma-carcinoma squence in representative examples of sporadic adenomatous lesion with low-grade dysplasia (LGD) (upper panel), sporadic adenomatous lesion with high-grade dysplasia (HGD) (middle panel), and sporadic invasive adenocarcinoma (ADC) (lower panel). Note the membranous and cytoplasmic immunoreactivity of MHC-I in neoplastic cells of HGD and invasive ADC lesions. Hematoxylin and eosin (left panel) and immunohistochemistry for MHC-I (middle panel) and PD-L1 (right panel), 40× amplification. The insets in the right panel represent higher magnification of PD-L1 immunohistochemistry, 400× amplification.
Overall, the increase in TMB in sporadic lesions, and the increase in MHC-I expression in both sporadic and FAP lesions along the ACS suggest that the observed decrease in immune cell counts cannot be explained by a loss of immunogenicity.

References

  1. Fearon, E.R.; Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 1990, 61, 759–767.
  2. Powell, S.M.; Zilz, N.; Beazer-Barclay, Y.; Bryan, T.M.; Hamilton, S.R.; Thibodeau, S.N.; Vogelstein, B.; Kinzler, K.W. APC mutations occur early during colorectal tumorigenesis. Nature 1992, 359, 235–237.
  3. Kinzler, K.W.; Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 1996, 87, 159–170.
  4. Cui, G.; Shi, Y.; Cui, J.; Tang, F.; Florholmen, J. Immune microenvironmental shift along human colorectal adenoma-carcinoma sequence: Is it relevant to tumor development, biomarkers and biotherapeutic targets? Scand. J. Gastroenterol. 2012, 47, 367–377.
  5. Nosho, K.; Baba, Y.; Tanaka, N.; Shima, K.; Hayashi, M.; Meyerhardt, J.A.; Giovannucci, E.; Dranoff, G.; Fuchs, C.S.; Ogino, S. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: Cohort study and literature review. J. Pathol. 2010, 222, 350–366.
  6. Jakubowska, K.; Kisielewski, W.; Kanczuga-Koda, L.; Koda, M.; Famulski, W. Diagnostic value of inflammatory cell infiltrates, tumor stroma percentage and disease-free survival in patients with colorectal cancer. Oncol. Lett. 2017, 14, 3869–3877.
  7. Pages, F.; Mlecnik, B.; Marliot, F.; Bindea, G.; Ou, F.S.; Bifulco, C.; Lugli, A.; Zlobec, I.; Rau, T.T.; Berger, M.D.; et al. International validation of the consensus Immunoscore for the classification of colon cancer: A prognostic and accuracy study. Lancet 2018, 391, 2128–2139.
  8. Le, D.T.; Uram, J.N.; Wang, H.; Bartlett, B.R.; Kemberling, H.; Eyring, A.D.; Skora, A.D.; Luber, B.S.; Azad, N.S.; Laheru, D.; et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N. Engl. J. Med. 2015, 372, 2509–2520.
  9. Golshani, G.; Zhang, Y. Advances in immunotherapy for colorectal cancer: A review. Ther. Adv. Gastroenterol. 2020, 13, 7527.
  10. Agarwal, P.; Le, D.T.; Boland, P.M. Immunotherapy in colorectal cancer. Adv. Cancer Res. 2021, 151, 137–196.
  11. Alexandrov, L.B.; Nik-Zainal, S.; Wedge, D.C.; Aparicio, S.A.; Behjati, S.; Biankin, A.V.; Bignell, G.R.; Bolli, N.; Borg, A.; Borresen-Dale, A.L.; et al. Signatures of mutational processes in human cancer. Nature 2013, 500, 415–421.
  12. Banner, B.F.; Savas, L.; Baker, S.; Woda, B.A. Characterization of the inflammatory cell populations in normal colon and colonic carcinomas. Virchows Arch. B Cell Pathol. 1993, 64, 213–220.
  13. McLean, M.H.; Murray, G.I.; Stewart, K.N.; Norrie, G.; Mayer, C.; Hold, G.L.; Thomson, J.; Fyfe, N.; Hope, M.; Mowat, N.A.; et al. The inflammatory microenvironment in colorectal neoplasia. PLoS ONE 2011, 6, e15366.
  14. Cui, G.; Yuan, A.; Vonen, B.; Florholmen, J. Progressive cellular response in the lamina propria of the colorectal adenoma-carcinoma sequence. Histopathology 2009, 54, 550–560.
  15. Cui, G.; Goll, R.; Olsen, T.; Steigen, S.E.; Husebekk, A.; Vonen, B.; Florholmen, J. Reduced expression of microenvironmental Th1 cytokines accompanies adenomas-carcinomas sequence of colorectum. Cancer Immunol. Immunother. 2007, 56, 985–995.
  16. Hua, W.; Yuan, A.; Zheng, W.; Li, C.; Cui, J.; Pang, Z.; Zhang, L.; Li, Z.; Goll, R.; Cui, G. Accumulation of FoxP3+ T regulatory cells in the tumor microenvironment of human colorectal adenomas. Pathol. Res. Pract. 2016, 212, 106–112.
  17. Cui, G. Immune battle at the premalignant stage of colorectal cancer: Focus on immune cell compositions, functions and cytokine products. Am. J. Cancer Res. 2020, 10, 1308–1320.
  18. Liu, F.; Hu, X.; Zimmerman, M.; Waller, J.L.; Wu, P.; Hayes-Jordan, A.; Lev, D.; Liu, K. TNFalpha cooperates with IFN-gamma to repress Bcl-xL expression to sensitize metastatic colon carcinoma cells to TRAIL-mediated apoptosis. PLoS ONE 2011, 6, e16241.
  19. Yang, J.; Wen, Z.; Li, W.; Sun, X.; Ma, J.; She, X.; Zhang, H.; Tu, C.; Wang, G.; Huang, D.; et al. Immune Microenvironment: New Insight for Familial Adenomatous Polyposis. Front. Oncol. 2021, 11, 570241.
  20. Liu, G.C.; Liu, R.Y.; Yan, J.P.; An, X.; Jiang, W.; Ling, Y.H.; Chen, J.W.; Bei, J.X.; Zuo, X.Y.; Cai, M.Y.; et al. The Heterogeneity Between Lynch-Associated and Sporadic MMR Deficiency in Colorectal Cancers. J. Natl. Cancer Inst. 2018, 110, 975–984.
  21. Morrison, B.J.; Steel, J.C.; Morris, J.C. Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cells. BMC Cancer 2018, 18, 469.
  22. McGranahan, N.; Furness, A.J.; Rosenthal, R.; Ramskov, S.; Lyngaa, R.; Saini, S.K.; Jamal-Hanjani, M.; Wilson, G.A.; Birkbak, N.J.; Hiley, C.T.; et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016, 351, 1463–1469.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Oncology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Irene Gullo
View Times: 401
Entry Collection: Gastrointestinal Disease
Revisions: 3 times (View History)
Update Date: 08 Oct 2021
Table of Contents
    1000/1000
    Hot Most Recent
    Feedback