CAMK1D triggers immune resistance of human tumor cells refractory to anti-PD-L1 treatment.

The success of cancer immunotherapy is limited by resistance to immune-checkpoint blockade. We therefore conducted a genetic screen to identify genes that mediated resistance against cytotoxic T lymphocytes (CTL) in anti-PD-L1 treatment refractory human tumors. Using PD-L1 positive multiple myeloma cells co-cultured with tumor-reactive bone marrow-infiltrating CTL as a model, we identified calcium/calmodulin-dependent protein kinase 1D (CAMK1D) as a key modulator of tumor intrinsic immune resistance. CAMK1D was co-expressed with PD-L1 in anti-PD-L1/PD-1 treatment refractory cancer types and correlated with poor prognosis in these tumors. CAMK1D was activated by CTL through Fas-receptor stimulation, which led to CAMK1D binding to and phosphorylating caspase -3, -6 and -7, inhibiting their activation and function. Consistently, CAMK1D mediated immune resistance of murine colorectal cancer cells in vivo. The pharmacological inhibition of CAMK1D on the other hand, restored the sensitivity towards Fas-ligand treatment in multiple myeloma and uveal melanoma cells in vitro. Thus, rapid inhibition of the terminal apoptotic cascade by CAMK1D expressed in anti-PD-L1 refractory tumors via T cell recognition may have contributed to tumor immune resistance.