Association between Intratumoral CD8+ T Cells with FoxP3+ and CD163+ Cells: A Potential Immune Intrinsic Negative Feedback Mechanism for Acquired Immune Resistance
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patient Selection and Characteristics
2.2. Assessment of Tumor-Infiltrating Leukocytes
2.3. Statistical Analysis
3. Results
3.1. Combined Intratumoral Analyses in TC and IM: Association between CD8+ and CD163+ or FoxP3+ Cell Densities
3.2. Combined Intratumoral Analyses in TC and IM: Association between CD8+ and Combined CD163+, FoxP3+ Cell Densities
3.3. Analyses in the TC or IM Separately
3.4. Correlations between CD8+ TC/IM Ratios and OS
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Spranger, S.; Gajewski, T.F. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat. Rev. Cancer 2018, 18, 139–147. [Google Scholar] [CrossRef] [PubMed]
- Sharma, P.; Hu-Lieskovan, S.; Wargo, J.A.; Ribas, A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell 2017, 168, 707–723. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Spranger, S.; Spaapen, R.M.; Zha, Y.; Williams, J.; Meng, Y.; Ha, T.T.; Gajewski, T.F. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci. Transl. Med. 2013, 5, 200ra116. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Williams, J.B.; Horton, B.L.; Zheng, Y.; Duan, Y.; Powell, J.D.; Gajewski, T.F. The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment. J. Exp. Med. 2017, 214, 381–400. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Grasso, C.S.; Giannakis, M.; Wells, D.K.; Hamada, T.; Mu, X.J.; Quist, M.; Nowak, J.A.; Nishihara, R.; Qian, Z.R.; Inamura, K.; et al. Genetic Mechanisms of Immune Evasion in Colorectal Cancer. Cancer Discov. 2018, 8, 730–749. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- DeLeeuw, R.J.; Kost, S.E.; Kakal, J.A.; Nelson, B.H. The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: A critical review of the literature. Clin. Cancer Res. 2012, 18, 3022–3029. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hamid, O.; Schmidt, H.; Nissan, A.; Ridolfi, L.; Aamdal, S.; Hansson, J.; Guida, M.; Hyams, D.M.; Gomez, H.; Bastholt, L.; et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J. Transl. Med. 2011, 9, 204. [Google Scholar] [CrossRef] [Green Version]
- Correale, P.; Rotundo, M.S.; Del Vecchio, M.T.; Remondo, C.; Migali, C.; Ginanneschi, C.; Tsang, K.Y.; Licchetta, A.; Mannucci, S.; Loiacono, L.; et al. Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J. Immunother. 2010, 33, 435–441. [Google Scholar] [CrossRef]
- Milne, K.; Kobel, M.; Kalloger, S.E.; Barnes, R.O.; Gao, D.; Gilks, C.B.; Watson, P.H.; Nelson, B.H. Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as positive prognostic factors. PLoS ONE 2009, 4, e6412. [Google Scholar] [CrossRef] [Green Version]
- Nonomura, N.; Takayama, H.; Nakayama, M.; Nakai, Y.; Kawashima, A.; Mukai, M.; Nagahara, A.; Aozasa, K.; Tsujimura, A. Infiltration of tumour-associated macrophages in prostate biopsy specimens is predictive of disease progression after hormonal therapy for prostate cancer. BJU Int. 2011, 107, 1918–1922. [Google Scholar] [CrossRef]
- Erlandsson, A.; Carlsson, J.; Lundholm, M.; Falt, A.; Andersson, S.O.; Andren, O.; Davidsson, S. M2 macrophages and regulatory T cells in lethal prostate cancer. Prostate 2019, 79, 363–369. [Google Scholar] [CrossRef] [PubMed]
- Zarif, J.C.; Baena-Del Valle, J.A.; Hicks, J.L.; Heaphy, C.M.; Vidal, I.; Luo, J.; Lotan, T.L.; Hooper, J.E.; Isaacs, W.B.; Pienta, K.J.; et al. Mannose Receptor-positive Macrophage Infiltration Correlates with Prostate Cancer Onset and Metastatic Castration-resistant Disease. Eur. Urol. Oncol. 2019, 2, 429–436. [Google Scholar] [CrossRef] [PubMed]
- Zhang, R.; Liu, Q.; Peng, J.; Wang, M.; Gao, X.; Liao, Q.; Zhao, Y. Pancreatic cancer-educated macrophages protect cancer cells from complement-dependent cytotoxicity by up-regulation of CD59. Cell Death Dis. 2019, 10, 836. [Google Scholar] [CrossRef] [Green Version]
- Larionova, I.; Tuguzbaeva, G.; Ponomaryova, A.; Stakheyeva, M.; Cherdyntseva, N.; Pavlov, V.; Choinzonov, E.; Kzhyshkowska, J. Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers. Front. Oncol. 2020, 10, 566511. [Google Scholar] [CrossRef] [PubMed]
- Shen, L.; Li, H.; Shi, Y.; Wang, D.; Gong, J.; Xun, J.; Zhou, S.; ** the Tumor Immune Landscape. Immunity 2018, 48, 399–416. [Google Scholar] [CrossRef] [Green Version]
- He, T.; Chen, Y.; Yang, D.; Islam, M.S.; Chou, C.K.; Liu, J.; Faustman, D.L.; Oppenheim, J.J.; Chen, X. TNFR2 antagonistic antibody induces the death of tumor infiltrating CD4(+)Foxp3(+) regulatory T cells. Cell Oncol. 2022. [Google Scholar] [CrossRef]
- Gao, R.; Shi, G.P.; Wang, J. Functional Diversities of Regulatory T Cells in the Context of Cancer Immunotherapy. Front. Immunol. 2022, 13, 833667. [Google Scholar] [CrossRef]
- Shen, X.; Zhou, S.; Yang, Y.; Hong, T.; **ang, Z.; Zhao, J.; Zhu, C.; Zeng, L.; Zhang, L. TAM-targeted reeducation for enhanced cancer immunotherapy: Mechanism and recent progress. Front. Oncol. 2022, 12, 1034842. [Google Scholar] [CrossRef] [PubMed]
- Peters, S.; Paz-Ares, L.; Herbst, R.S.; Reck, M. Addressing CPI resistance in NSCLC: Targeting TAM receptors to modulate the tumor microenvironment and future prospects. J. Immunother. Cancer 2022, 10, e004863. [Google Scholar] [CrossRef] [PubMed]
- Guerriero, J.L. Macrophages: The Road Less Traveled, Changing Anticancer Therapy. Trends Mol. Med. 2018, 24, 472–489. [Google Scholar] [CrossRef] [PubMed]
- Christmas, B.J.; Rafie, C.I.; Hopkins, A.C.; Scott, B.A.; Ma, H.S.; Cruz, K.A.; Woolman, S.; Armstrong, T.D.; Connolly, R.M.; Azad, N.A.; et al. Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs. Cancer Immunol. Res. 2018, 6, 1561–1577. [Google Scholar] [CrossRef] [Green Version]
- Kim, K.; Skora, A.D.; Li, Z.; Liu, Q.; Tam, A.J.; Blosser, R.L.; Diaz, L.A., Jr.; Papadopoulos, N.; Kinzler, K.W.; Vogelstein, B.; et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc. Natl. Acad. Sci. USA 2014, 111, 11774–11779. [Google Scholar] [CrossRef] [Green Version]
- Orillion, A.; Hashimoto, A.; Damayanti, N.; Shen, L.; Adelaiye-Ogala, R.; Arisa, S.; Chintala, S.; Ordentlich, P.; Kao, C.; Elzey, B.; et al. Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma. Clin. Cancer Res. 2017, 23, 5187–5201. [Google Scholar] [CrossRef] [Green Version]
- Jenkins, R.W.; Barbie, D.A.; Flaherty, K.T. Mechanisms of resistance to immune checkpoint inhibitors. Br. J. Cancer 2018, 118, 9–16. [Google Scholar] [CrossRef] [Green Version]
- Mahoney, K.M.; Rennert, P.D.; Freeman, G.J. Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 2015, 14, 561–584. [Google Scholar] [CrossRef]
- Stockis, J.; Lienart, S.; Colau, D.; Collignon, A.; Nishimura, S.L.; Sheppard, D.; Coulie, P.G.; Lucas, S. Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin alphaVbeta8. Proc. Natl. Acad. Sci. USA 2017, 114, E10161–E10168. [Google Scholar] [CrossRef] [Green Version]
- Feng, X.; Zhang, L.; Acharya, C.; An, G.; Wen, K.; Qiu, L.; Munshi, N.C.; Tai, Y.T.; Anderson, K.C. Targeting CD38 Suppresses Induction and Function of T Regulatory Cells to Mitigate Immunosuppression in Multiple Myeloma. Clin. Cancer Res. 2017, 23, 4290–4300. [Google Scholar] [CrossRef]
Total Number of Patients | |
---|---|
n = 97 | |
Median age (years) | Range |
53 | 32–78 |
Tumor size | n |
Tx | 1 |
T1 | 39 |
T2 | 50 |
T3 | 7 |
LN status | n |
N0 | 38 |
N1 | 34 |
N2 | 18 |
N3 | 7 |
AJCC stage (TNM) | n |
I | 25 |
IIA | 25 |
IIB | 20 |
IIIA | 19 |
IIIB | X * |
IIIC | 8 |
Grade | n |
1 | 3 |
2 | 56 |
3 | 38 |
Hormone receptor | n |
positive | 74 |
negative | 23 |
HER-2/neu | n |
positive | 23 |
negative | 74 |
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Fortis, S.P.; Sofopoulos, M.; Goulielmaki, M.; Arnogiannaki, N.; Ardavanis, A.; Perez, S.A.; Gritzapis, A.D.; Baxevanis, C.N. Association between Intratumoral CD8+ T Cells with FoxP3+ and CD163+ Cells: A Potential Immune Intrinsic Negative Feedback Mechanism for Acquired Immune Resistance. Cancers 2022, 14, 6208. https://doi.org/10.3390/cancers14246208
Fortis SP, Sofopoulos M, Goulielmaki M, Arnogiannaki N, Ardavanis A, Perez SA, Gritzapis AD, Baxevanis CN. Association between Intratumoral CD8+ T Cells with FoxP3+ and CD163+ Cells: A Potential Immune Intrinsic Negative Feedback Mechanism for Acquired Immune Resistance. Cancers. 2022; 14(24):6208. https://doi.org/10.3390/cancers14246208
Chicago/Turabian StyleFortis, Sotirios P., Michael Sofopoulos, Maria Goulielmaki, Niki Arnogiannaki, Alexandros Ardavanis, Sonia A. Perez, Angelos D. Gritzapis, and Constantin N. Baxevanis. 2022. "Association between Intratumoral CD8+ T Cells with FoxP3+ and CD163+ Cells: A Potential Immune Intrinsic Negative Feedback Mechanism for Acquired Immune Resistance" Cancers 14, no. 24: 6208. https://doi.org/10.3390/cancers14246208