Collaborative Project #1: Foundations of microbiome in anti-tumor immune responses
Collaborating Investigator: Tim Chan, MD PhD
Affiliation: Memorial Sloan Kettering
Vice Chair, Dept. of Radiation Oncology Human Oncology and Pathogenesis Program
Funding Source: NIH
Grant Number: R01CA177828
Project Period: 02/01/15-01/31/20
New agents that block immune checkpoints have the potential to revolutionize the treatment of cancers. Anti-CTLA4 and anti-PD-1 antibodies show significant promise in clinical trials. However, the molecular determinants of response are unknown. The mechanism of checkpoint blockade remains one of the most important unanswered questions in oncology. Our preliminary data demonstrate that therapeutic response is determined strongly by tumor genome and homology with foreign antigens present in the microbiome. Here, we seek to define the molecular determinants that define T cell receptor sensitivity for neoantigen and the role of foreign pathogen antigens in stimulating those responses.
Aim 1: Define the neoantigen landscape and anti-tumor T cell response that predict efficacy of immune checkpoint blockade therapy by neoantigen similarity with foreign antigen. Using whole exome sequencing, we identified and validated neoantigen responses homologous to pathogenB. pertussisin a non-small cell lung cancer patients who respond to anti-PD1 treatmentwho have both HLA A11 andHLAB07-specific responses.We will create a humanized A11-HERC1and B07-nano-aAPC for expansion studies and cross reactivity to B. pertussisfrom patient blood after treatment.
Aim 2: Using a model neoepitope antigen Kb-SIY in murine melanoma model B16-SIY and Kb-SIYTCR redundancy with B. fido, we will measure Kb-SIY anti-tumor response and repertoire changes in Kb-SIY aAPC expanded cells in the presence or absence of B. fido exposure. Our preliminary data shows that E+E stimulates T cells using either Kb-SIY or Kb-SVY nano-aAPC and that these T cells are cross-reactive(see attached figure). This confirms that there is clear overlap between the two responses.We will further elucidate the affinity response for the cross-reactivity and the clonal diversity of Kb-SIY with and without pathogen influence in both naïve repertoire and after tumor exposure. We propose that this could serve as a model antigen to illustrate the mechanism of action of pathogen-neoantigen homology on anti-tumor response resistance.
While the Schneck lab has extensively used nano-aAPCs for classic Kb-SIY antigen-based E+E expansion using SIY-peptide loaded H2Kb-specific aAPC, they have not targeted antigen responses based on microbiome exposure. For the push-pull relationship, the Schneck lab will study E+E as described in TR&D1 and Chan lab will compare E+E using the system described, above, to B. Fido pulsed DC. In addition, the Chan lab will alter the microbiome of specific B6 mice, from Jax and Taconic, and Schneck lab will study E+E based expansion from mice with different microbiomes. Another example of the push-pull relationship is if alterations in the microbiome change nano-aAPC requirements for signal 2 choice or ligand density. Weexpect that this will be a very active push-pull collaborative relationship studying the influence of the microbiome and model neoepitope ant-cancer responses. The push-pull relationship will also entail developing two new HLA A11and HLA B0702-based aAPC based nano-APC for expansion of T cell populations in patient samples. The experiments in TR&D1 will be used to model similar push-pull experiments studying the relationship of human neoepitope specific T cells in lung cancer.