Tumor Resident Memory CD8 T Cells and Concomitant Tumor Immunity Develop Independently of CD4 Help

Overview

Journal Sci Rep

Specialty Science

Date 2023 Apr 18

PMID 37072485

Authors

Terry R Medler

Gwen Kramer

Shelly Bambina

Andrew J Gunderson

Alejandro Alice

Tiffany Blair

Lauren Zebertavage

Thomas Duhen

Rebekka Duhen

Kristina Young

Marka R Crittenden

Michael J Gough

Affiliations

Soon will be listed here.

Abstract

Tissue resident memory (Trm) CD8 T cells infiltrating tumors represent an enriched population of tumor antigen-specific T cells, and their presence is associated with improved outcomes in patients. Using genetically engineered mouse pancreatic tumor models we demonstrate that tumor implantation generates a Trm niche that is dependent on direct antigen presentation by cancer cells. However, we observe that initial CCR7-mediated localization of CD8 T cells to tumor draining lymph nodes is required to subsequently generate CD103 CD8 T cells in tumors. We observe that the formation of CD103 CD8 T cells in tumors is dependent on CD40L but independent of CD4 T cells, and using mixed chimeras we show that CD8 T cells can provide their own CD40L to permit CD103 CD8 T cell differentiation. Finally, we show that CD40L is required to provide systemic protection against secondary tumors. These data suggest that CD103 CD8 T cell formation in tumors can occur independent of the two-factor authentication provided by CD4 T cells and highlight CD103 CD8 T cells as a distinct differentiation decision from CD4-dependent central memory.

Citing Articles

Comprehensive analysis of mitochondrial-related gene signature for prognosis, tumor immune microenvironment evaluation, and candidate drug development in colon cancer.

Wu H, Zhang W, Chang J, Wu J, Zhang X, Jia F Sci Rep. 2025; 15(1):6173.

PMID: 39979377 PMC: 11842742. DOI: 10.1038/s41598-024-85035-2.

Depletion of conventional CD4 T cells is required for robust priming and dissemination of tumor antigen-specific CD8 T cells in the setting of anti-CD4 therapy.

Ramirez D, Dragnev C, Searles T, Spicer N, Chen T, Lines J J Immunother Cancer. 2024; 12(11).

PMID: 39521617 PMC: 11552015. DOI: 10.1136/jitc-2024-010170.

Higher frequency of peripheral blood CD103CD8 T cells with lower levels of PD-1 and TIGIT expression related to favorable outcomes in leukemia patients.

Liu L, Lai W, Zhuo X, Chen S, Luo X, Tan H Front Immunol. 2024; 15:1437726.

PMID: 39391310 PMC: 11465237. DOI: 10.3389/fimmu.2024.1437726.

Enhancing radiotherapy response via intratumoral injection of a TLR9 agonist in autochthonous murine sarcomas.

Su C, Kent C, Pierpoint M, Floyd W, Luo L, Williams N JCI Insight. 2024; 9(14).

PMID: 39133651 PMC: 11383182. DOI: 10.1172/jci.insight.178767.

Crosstalking with Dendritic Cells: A Path to Engineer Advanced T Cell Immunotherapy.

Schafer S, Chen K, Ma L Front Syst Biol. 2024; 4.

PMID: 38911455 PMC: 11192543. DOI: 10.3389/fsysb.2024.1372995.

References

Zheng W, Skowron K, Namm J, Burnette B, Fernandez C, Arina A . Combination of radiotherapy and vaccination overcomes checkpoint blockade resistance. Oncotarget. 2016; 7(28):43039-43051. PMC: 5190006. DOI: 10.18632/oncotarget.9915. View

Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf E . CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell. 1999; 99(1):23-33. DOI: 10.1016/s0092-8674(00)80059-8. View

Blair T, Bambina S, Alice A, Kramer G, Medler T, Baird J . Dendritic Cell Maturation Defines Immunological Responsiveness of Tumors to Radiation Therapy. J Immunol. 2020; 204(12):3416-3424. PMC: 7571541. DOI: 10.4049/jimmunol.2000194. View

Kok L, Masopust D, Schumacher T . The precursors of CD8 tissue resident memory T cells: from lymphoid organs to infected tissues. Nat Rev Immunol. 2021; 22(5):283-293. PMC: 8415193. DOI: 10.1038/s41577-021-00590-3. View

Crittenden M, Zebertavage L, Kramer G, Bambina S, Friedman D, Troesch V . Tumor cure by radiation therapy and checkpoint inhibitors depends on pre-existing immunity. Sci Rep. 2018; 8(1):7012. PMC: 5934473. DOI: 10.1038/s41598-018-25482-w. View

Galvez-Cancino F, Lopez E, Menares E, Diaz X, Flores C, Caceres P . Vaccination-induced skin-resident memory CD8 T cells mediate strong protection against cutaneous melanoma. Oncoimmunology. 2018; 7(7):e1442163. PMC: 5993487. DOI: 10.1080/2162402X.2018.1442163. View

Duhen T, Gough M, Leidner R, Stanton S . Development and therapeutic manipulation of the head and neck cancer tumor environment to improve clinical outcomes. Front Oral Health. 2022; 3:902160. PMC: 9354490. DOI: 10.3389/froh.2022.902160. View

Moore M, Carbone F, Bevan M . Introduction of soluble protein into the class I pathway of antigen processing and presentation. Cell. 1988; 54(6):777-85. DOI: 10.1016/s0092-8674(88)91043-4. View

Schoenberger S, Toes R, van der Voort E, Offringa R, Melief C . T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature. 1998; 393(6684):480-3. DOI: 10.1038/31002. View

10.

Keenan B, Saenger Y, Kafrouni M, Leubner A, Lauer P, Maitra A . A Listeria vaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice. Gastroenterology. 2014; 146(7):1784-94.e6. PMC: 4035450. DOI: 10.1053/j.gastro.2014.02.055. View

11.

Lees J, Charbonneau B, Swanson A, Jensen R, Zhang J, Matusik R . Deletion is neither sufficient nor necessary for the induction of peripheral tolerance in mature CD8+ T cells. Immunology. 2006; 117(2):248-61. PMC: 1782220. DOI: 10.1111/j.1365-2567.2005.02293.x. View

12.

Zebertavage L, Alice A, Crittenden M, Gough M . Transcriptional Upregulation of NLRC5 by Radiation Drives STING- and Interferon-Independent MHC-I Expression on Cancer Cells and T Cell Cytotoxicity. Sci Rep. 2020; 10(1):7376. PMC: 7193601. DOI: 10.1038/s41598-020-64408-3. View

13.

Stark R, Hartung A, Zehn D, Frentsch M, Thiel A . IL-12-mediated STAT4 signaling and TCR signal strength cooperate in the induction of CD40L in human and mouse CD8+ T cells. Eur J Immunol. 2013; 43(6):1511-7. DOI: 10.1002/eji.201243218. View

14.

Osborn J, Hobbs S, Mooster J, Khan T, Kilgore A, Harbour J . Central memory CD8+ T cells become CD69+ tissue-residents during viral skin infection independent of CD62L-mediated lymph node surveillance. PLoS Pathog. 2019; 15(3):e1007633. PMC: 6420010. DOI: 10.1371/journal.ppat.1007633. View

15.

Marzo A, Vezys V, Klonowski K, Lee S, Muralimohan G, Moore M . Fully functional memory CD8 T cells in the absence of CD4 T cells. J Immunol. 2004; 173(2):969-75. DOI: 10.4049/jimmunol.173.2.969. View

16.

Behr F, Parga-Vidal L, Kragten N, van Dam T, Wesselink T, Sheridan B . Tissue-resident memory CD8 T cells shape local and systemic secondary T cell responses. Nat Immunol. 2020; 21(9):1070-1081. DOI: 10.1038/s41590-020-0723-4. View

17.

Zebertavage L, Bambina S, Shugart J, Alice A, Zens K, Lauer P . A microbial-based cancer vaccine for induction of EGFRvIII-specific CD8+ T cells and anti-tumor immunity. PLoS One. 2019; 14(1):e0209153. PMC: 6314576. DOI: 10.1371/journal.pone.0209153. View

18.

Shields B, Koss B, Taylor E, Storey A, West K, Byrum S . Loss of E-Cadherin Inhibits CD103 Antitumor Activity and Reduces Checkpoint Blockade Responsiveness in Melanoma. Cancer Res. 2019; 79(6):1113-1123. PMC: 6420873. DOI: 10.1158/0008-5472.CAN-18-1722. View

19.

Shugart J, Bambina S, Alice A, Montler R, Bahjat K . A self-help program for memory CD8+ T cells: positive feedback via CD40-CD40L signaling as a critical determinant of secondary expansion. PLoS One. 2013; 8(5):e64878. PMC: 3662717. DOI: 10.1371/journal.pone.0064878. View

20.

Hanninen A, Maksimow M, Alam C, Morgan D, Jalkanen S . Ly6C supports preferential homing of central memory CD8+ T cells into lymph nodes. Eur J Immunol. 2011; 41(3):634-44. DOI: 10.1002/eji.201040760. View