2018 – TET2-MUTANT CLONAL HEMATOPOIESIS REPROGRAMS THE TUMOUR MICROENVIRONMENT TO PROMOTE IMMUNOTHERAPY RESPONSE

Clonal hematopoiesis is common in solid tumour patients, who frequently have loss of function mutations in TET2. TET2 restricts innate and adaptive immunity, so we hypothesized that TET2-mutant clonal hematopoiesis (TET2-CH) is associated with immunotherapy response. To test this hypothesis, syngeneic colorectal cancer-bearing mice with Tet2-heterozygous null (Tet2-het) or wild type hematopoiesis were treated with anti-PD-1 immunotherapy. Treatment responses were greater and tumors were smaller in Tet2-het mice. The Tet2-effect required phagocytes, CD4, and CD8 T cells, but not NK cells. scRNA-seq revealed how Tet2-mutations reshape the tumor-infiltrating cell (TIL) landscape with immunotherapy by inducing anti-tumour states and restricting pro-tumour cell states. Tet2-mutant monocytes upregulated T cell costimulatory genesets and we found enhanced communication between Tet2-het antigen presenting and T cells. Combined sc-genotyping and RNA-seq of primary TET2-CH patient leukocytes showed that, like mouse TILs, human TET2-mutant monocytes upregulated costimulatory and inflammatory programs associated with immunotherapy response. TET2-mutant CD8 T cells were rare but strikingly enriched for memory programs and TCR signaling, yet suppressed an exhaustion signature. Melanoma patient RNA-seq showed TET2-CH+ tumours are enriched for antigen presentation/costimulation and T cell memory versus exhaustion. TET2-CH+ melanomas also had increased immune infiltrate, T cells and dendritic cells, and re-analysis of 200 immunotherapy-treated melanoma patients showed those with TET2-CH were 6-fold more likely to benefit from immunotherapy. Therefore, across mouse tumours, human leukocytes and tumours, somatic TET2-mutations activate transcriptional programs in myeloid and T cells associated with anti-tumour immunity, which correlate with enhanced immunotherapy response in melanoma.