Understanding the induction of T cell dysfunction in the context of lung cancer

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Project Summary Cancer immunotherapy, foremost checkpoint blockade therapy (CBT), has revolutionized the landscape of cancer treatment. However, to date only a minority of cancer patients is experiencing a long-term clinical benefit, while the majority of patients does not respond or progresses upon initial response. Thus far, a lack of infiltration with tumor-reactive T cells is a highly correlative marker for the lack of sensitivity to CBT, such as anti-PD-1. However, the reverse conclusion that a tumor-reactive T cell infiltrate would be predictive for an anti-tumor immune response does not always stand its ground. In patients with non-small cell lung cancer (NSCLC) only half of the patients with a detectable tumor-reactive T cell infiltrate respond to CBT. Especially NSCLC driven by oncogenic KRAS mutations in combination with p53-loss are frequently refractory to CBT. This observation poses the critical question as to which additional mechanisms mediating resistance to CBT in T cell infiltrated NSCLC subsets, and potentially also other cancer types. Further, it raises the possibility that anti-tumor immune responses may be dominantly affected by the organs’ specific immune microenvironment. To specifically address this notion, we have established a mouse model of KRAS/p53-driven lung adenocarcinoma, that is resistant to CBT but at the same time shows infiltration with effector CD8+ T cells. Our data suggest, that despite a high degree of T cell infiltration the CD8+ T cells infiltrating lung tumors are intrinsically dysfunctional, rendering the T cell response incapable of eradicating tumor cells. These differences were found to be independent of the tumor-specific antigen and rather imprinted at the time of T cell activation in the lung tumor-draining mediastinal lymph node. Further, the lung tumor-specific T cell dysfunction observed is strikingly different to the conventional T cell exhaustion phenotype often described as PD1+, Lag3+, Tim3+, and highly sensitive to CBT therapy. Based on these observations it is our central hypothesis that lung-specific T cell dysfunction is a unique and persisting state of T cell activation, induced by lung-derived dendritic cells during priming in the mediastinal lymph node and characterized by impaired anti-tumor effector function. By determining the immunological underpinnings that are responsible for the observed T cell dysfunction (Aim 1) and stimulatory capacity of dendritic cells (Aim 2), we will be able to elucidate yet undiscovered immune suppression mechanisms mediating immune evasion in T cell-inflamed tumors. By better understanding how lung-restricted anti-tumor immunity is induced we will be able to facilitate the development of novel immunotherapies. While this grant will focus on lung cancer it is conceivable that any identified mechanisms are more broadly applicable. The ultimate premise will always be to increase the number of patients with a durable anti-tumor immune response and long-term, durable clinical benefits.