Tumor masses support naive T cell infiltration, activation, and differentiation into effectors

Abstract

Studies of T cell responses to tumors have focused on the draining lymph node (LN) as the site of activation. We examined the tumor mass as a potential site of activation after adoptive transfer of naive tumor-specific CD8 T cells. Activated CD8 T cells were present in tumors within 24 h of adoptive transfer and proliferation of these cells was also evident 4–5 d later in mice treated with FTY720 to prevent infiltration of cells activated in LNs. To confirm that activation of these T cells occurred in the tumor and not the tumor-draining LNs, we used mice lacking LNs. Activated and proliferating tumor-infiltrating lymphocytes were evident in these mice 24 h and 4 d after naive cell transfer. T cells activated within tumors acquired effector function that was evident both ex vivo and in vivo. Both cross-presenting antigen presenting cells within the tumor and tumor cells directly presenting antigen activated these functional CD8 effectors. We conclude that tumors support the infiltration, activation, and effector differentiation of naive CD8 T cells, despite the presence of immunosuppressive mechanisms. Thus, targeting of T cell activation to tumors may present a tool in the development of cancer immunotherapy.

Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy

“…Modulations of the immunologic conditions at the tumor site are gaining increasing interest, as it has been recognized that solid tumors constitute an important place for the initiation and development of an antitumor immune response. For example, it was shown in mouse models that na€ ve CD8 þ T cells can infiltrate tumors and become activated and differentiated into functional effector cells in situ (53). Studies in mice provided evidence that localized activity of IL-15 and 4-1BB in the tumor microenvironment was relevant for the respective antitumor response (54,55).…”

Progression of carcinogen‐induced fibrosarcomas is associated with the accumulation of naïve CD4+ T cells via blood vessels and lymphatics

“…Similarly, delivery of lymphotoxin‐α fused to tumor‐specific antibodies induces HEV development in B16 melanoma, resulting in infiltration and priming of effective antitumor T cells 26. In another study, adoptively transferred naïve transgenic T cells were shown to infiltrate tumors where they became activated and proliferated in response to antigens presented by cells within the tumor parenchyma 27. These reports are interesting as they demonstrate the potential for T‐cell priming in tumors and the capacity for this event to contribute to control of tumor growth.…”

Innate immune signaling and regulation in cancer immunotherapy

“…In addition to the classical notion that the site for activation of tumor-specific CD8 + T cells is the tumor-draining lymph node, cross-priming of naive CD8 + T cells has also been reported to occur in the tumor microenvironment [48]. This appears to be due to the presence in the tumors of vasculature resembling the high endothelial venules characteristic of lymph nodes.…”

“…This appears to be due to the presence in the tumors of vasculature resembling the high endothelial venules characteristic of lymph nodes. Through the expression of peripheral node addressins (PNAd) and CCL21 on the luminal endothelial surface, these blood vessels supported the extravasation of naive CD8 + T cells, which were subsequently activated in the tumor [48,49]. Thus, intratumoral expression of type I IFNs may even prompt tumor-infiltrating Batf3 DCs to cross-prime naive CD8 + T cells in the tumor, bypassing the need for migration to the draining lymph nodes.…”