Abstract B35: Dynamics of MHC class II tumor antigen presentation is critical for effector antitumor CD4+ T-cell generation and tumor rejection

Absence of CD4+ T cell help leads to defects in CD8+ T cell memory responses.Although this phenomenon is well characterized in infectious immunity, little is known about the generation of anti-tumor CD4+ T cell responses in vivo, or even how relevant is T cell help for tumor elimination. CD4+ T cells appear differ from CD8+ T cells in their requirements for differentiation, the dynamics of encounter with antigen being critical in this process. We analyzed the relevance of MHC class II antigen presentation for tumor rejection, developing a B16EaRFP line to study class II restricted tumor antigen presentation and the cognate CD4+ T cell help in vivo . We found that, in a tumor heavily infiltrated by dendritic cells (DC), a progressive decline in different cell subpopulations is observed in draining lymph nodes (DLNs), suggesting an interruption of local cell traffic. Artificial increase in precursor frequency of tumor specific CD8+ T cells by adoptive transfer of naive OT-I cells in C57Bl/6 mice injected with B16OVA tumor was able to delay tumor growth, but was not sufficient to block it completely. While tumor antigen presentation in class II molecules was detected in the DLN, and could be increased by delivery of necrotic or apoptotic tumor cells, tumor specific CD4+ T cells showed proliferation arrest in the DLN. Tumor growth was blocked only when dendritic cells (DCs) were activated by intra-tumoral LPS injection, reestablishing cell traffic to the LN, resulting in expansion of INF‐γ producing anti-tumor CD4+ T cells. Our results suggest that CD4+ T cells are a major target of tumor mediated antigen presentation interruption, and that CD4+ T cell help is necessary for rejection of an established tumor. These observations have major implications for the design of cancer immunotherapy strategies. Citation Information: Cancer Res 2009;69(23 Suppl):B35.