Rhabdoid Tumors Are Immunogenic and May Respond to Immunotherapy

Low tumor mutational burden (TMB) is associated with low expression levels of tumor-associated antigens; in principle, this should result in a reduced response to immune-checkpoint blockade (ICB). However, Leruste and colleagues found that this may not apply to rhabdoid tumors, a group of pediatric soft-tissue cancers with very low TMB. An analysis of 114 samples from both extracranial (ECRT) and intracranial (AT/RT) primary rhabdoid tumors revealed greater immune-cell infiltration in the ECRT, MYC-AT/RT, and TYR-AT/RT subgroups than in the SHH-AT/RT subgroup. Further, the extent of immune-related cytolytic activity among the non-SHH rhabdoid tumors matched that of some of the most immunogenic known tumor types (e.g., adult lung adenocarcinoma and melanoma). The rhabdoid tumors were infiltrated by large numbers of both T-cell and myeloid-cell populations, and the phenotypes of these immune cells implied an active and ongoing local antitumor response. The tumor immune infiltrates of the ECRT and MYC-AT/RT subgroups exhibited marked clonal expansions of tumor-resident and exhausted memory CD8⁺ T cells, probably resulting from a tumor-specific response by the adaptive immune system. Notably, tumor-infiltrating CD8⁺ T cells had high expression of clinically targetable inhibitory immune-checkpoint receptors, including PD-1, TIM3, and LAG3. This observation prompted experiments probing whether rhabdoid tumors were susceptible to ICB. In a mouse MYC-AT/RT model, PD-1 blockade prolonged survival and caused complete tumor regression in 67% to 80% of treated mice. Upon rechallenge using syngeneic grafts of the same tumor type, all cured mice rejected the new tumors, indicating that the treatment had resulted in immunity. Mechanistically, re-expression of endogenous retroviruses resulting from deficiency of the SWI–SNF complex component SMARCB1—some mutations in which are known to drive rhabdoid-tumor development—appeared to contribute to activation of the immune response in rhabdoid tumors. Together, these results suggest that immunotherapy may be more effective than would have been predicted for rhabdoid tumors and add to a growing body of evidence that the immunogenicity of tumors is not solely dictated by TMB.

Leruste A, Tosello J, Ramos RN, Tauziède-Espariat A, Brohard S, Han ZY, et al. Clonally expanded T cells reveal immunogenicity of rhabdoid tumors. Cancer Cell 2019;36:597–612.e8.

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