Uveal Melanoma Immunogenomics Predict Immunotherapy Resistance and Susceptibility

Abstract

Immunotherapy targeting immune checkpoint molecules can induce regression of metastatic cutaneous melanoma and improve patient survival. Unfortunately, this therapeutic approach has not shown comparable activity against most other solid tumors, especially those with low tumor mutational burden. We postulated that focused studies of uveal melanoma (UM), a treatment resistant variant with few somatic mutations, may provide generalized insights to develop improved therapeutics for immunotherapy resistant cancers. Here, we report comprehensive immunogenomic profiling on a large and diverse group of human UM metastases (n=100) using bulk and single cell transcriptomics, T cell receptor (TCR) repertoire analysis, tumor infiltrating lymphocyte (TIL) potency assessment, and analysis of an adoptive transfer clinical trial. Our findings reveal that over half of UM metastases harbor tumor infiltrating lymphocytes (TIL) with potent tumor specificity, despite these samples having low mutational burden and being refractory to immune checkpoint inhibition (ICI) and the bispecific T cell engager, tebentafusp. These T cell-inflamed metastases displayed activated antigen presenting cells, evidence of chronic interferon signaling, and diverse TCR repertoires. However, we found a striking lack of intratumoral TCR clonality indicative of growth suppression within the tumor microenvironment, despite receiving ICI and tebentafusp therapy. To harness the therapeutic potential of these endogenous T cells, we developed an unbiased whole-tumor transcriptomic biomarker to enable rapid in situ identification and ex vivo expansion of tumor reactive TIL. Transcriptomic profiling of metastatic tumor biopsies could accurately identify T cell-inflamed UM metastases that generated TIL with clinical anti-tumor efficacy after adoptive immunotherapy. Taken together, we reveal that metastatic UM is not an immunologically ‘cold’ cancer, but rather one that demonstrates occult immune priming and T cell recruitment that are not sufficiently exploited with current immunotherapies. We anticipate in situ immunogenomic profiling to identify these potent TIL and ex vivo expansion to counteract their suppressed growth will be necessary to promote tumor immunity. We are now prospectively evaluating transcriptomic guided adoptive TIL therapy as a therapeutic approach for metastatic UM and other immunotherapy resistant cancers. This will have public health significance by creating treatment opportunities for a large group of cancer patients who currently lack effective therapeutic options