CD8 T cell Activation In Cancer Is Comprised Of Two Distinct Phases Open Access

Prokhnevska, Nataliya (Fall 2022)

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The CD8 T cell response to tumors is extremely variable with heterogenous T cell subsets, a stem-like CD8 T cell (PD1+TCF1+) that sustains the CD8 response and gives rise to a terminally differentiated (TD) cytotoxic cell (TCF1-Tim3+). Although these subsets have been described, how tumor-specific CD8 T cells are activated and differentiate in tumors are not well defined. Using a prostate cancer model that expresses the LCMV-GP (TRAMPC1-GP), we studied tumor-specific CD8 T cell activation by transferring LCMV-GP specific P14 CD8 T cells into tumor-bearing mice. We found that P14s are activated in the tumor-draining LNs (TDLNs) and acquire a stem-like phenotype. These cells migrate into the tumor as stem-like CD8 T cells and only differentiate into a TD CD8 T cell in the tumor. We found that stem-like CD8 T cells need additional co-stimulation from antigen presenting cells within the tumor to fully differentiate, even though they have been previously activated in TLDNs. Similarly, stem-like CD8s from human kidney cancer require both TCR and co-stimulatory signals to divide and differentiation ex-vivo and can differentiate when co-cultured with autologous dendritic cells. The addition of IL12 with TCR alone was not sufficient to induce differentiation, but improved differentiation when co-stimulation was present. This demonstrates the necessity of additional TCR and co-stimulation once activated stem-like CD8 T cells migrate into the tumor. Overall, these data suggest two distinct phases of CD8 T cell differentiation, the first occurs in the TDLN where they are initially activated. The second occurs in the tumor, where they require additional co-stimulation to differentiate and acquire an effector phenotype.


Table of Contents


Introduction (1-11)

-         Immune response to viral infections (1-5)

-         CD8 T cells in cancer and chronic infections (5-10)

-         Unanswered questions in tumor immunology (11)

Part 1: CD8 T cells activate in tumor draining lymph nodes to acquire a stem-like phenotype (12-41)

-         1.1: Introduction (13-14)

-         1.2: Results (14-22)

-         1.3: Discussion (22-25)

-         1.4: Materials and methods (25-29)

-         1.6: Figures (30-35)

-         1.7 Supplemental Figures (36-41)

Part 2: LN-Stem CD8 T cells give rise to tumor infiltrating CD8 T cells (42-55)

-         2.1: Introduction (43-44)

-         2.2: Results (45-47)

-         2.3: Discussion (47-51)

-         2.4: Materials and methods (51)

-         2.5: Figures (52-53)

-         2.6: Supplemental Figures (54-55)

Part 3: Antigen presenting cell phenotype in tumors predict CD8 T cell differentiation (56-84)

-         3.1: Introduction (57-61)

o  Lymphoid organization in tumors

o  Antigen presenting cells in cancer

-         3.2: Results (61-67)

-         3.3: Discussion (67-71)

-         3.4: Materials and methods (71-73)

-         3.5: Figures (73-78)

-         3.6: Supplemental Figures (79-84)

Discussion (85-97)

-         Differences between viral infections and tumor initiation and innate immune response (86-90)

-         Implication of two phases of T cell activation on immunotherapy (86-90)

-         Conclusions (98-99)

References (100-105)

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