Tumor-Initiating Stem Cells Are Resistant to Immunotherapy

Tumor-initiating stem cells (tSC) possess the ability to self-renew and differentiate at low numbers, granting them the capacity for tumor growth and relapse following therapy. Despite their suspected role in resistance to immunotherapies such as adoptive cell transfer (ACT), the precise mechanisms by which tSCs escape immune surveillance remain unknown. Miao and colleagues utilized an immunotherapy-responsive mouse model of squamous cell carcinoma (SCC) to show that tSCs evade immune detection and initiate tumor relapse following ACT. Injection of tumor-specific cytotoxic T lymphocytes (CTL) resulted in robust infiltration into the tumor and significant reduction of tumor volume. Residual tumor cells persisted beyond the point of CTL exhaustion and survived a second treatment of ACT. Single-cell RNA sequencing of residual tumor cells identified a distinct cluster of tSCs expressing TGFβ with reduced expression of proinflammatory cytokines, chemokines, and proapoptotic genes. These tSCs also expressed CD80, a surface ligand that binds to the immune checkpoint protein CTLA4. Treatment with a TGFβ-blocking antibody reduced surface CD80 expression in tSCs, and treatment with a CTLA4-blocking antibody reinvigorated CTL activity against CD80⁺ SCC cells in vitro and blunted SCC tumor growth in vivo. Genetic ablation of Cd80 in vivo impaired tumor growth and enhanced CTL infiltration, proliferation, and antitumor activity, and specific deletion of Cd80 or Ctla4 in TGFβ-expressing tSCs resulted in more frequent and more active CTLs with diminished expression of inhibitory receptors, resulting in increased apoptosis in tSCs, decreased tSC survival, and diminished tumor relapse following ACT. Taken together, these findings establish a role for CD80 in tSC resistance to immunotherapy and highlight several potential therapeutic strategies to overcome this resistance.

Miao Y, Yang H, Levorse J, Yuan S, Polak L, Sribour M, et al. Adaptive immune resistance emerges from tumor-initiating stem cells. Cell 2019;177:1172–86.

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