Drug resistance is a major problem in cancer treatment. Over the last decade immune check point blockade (ICB) using antibodies against immune checkpoint proteins, such as programmed death-1 (PD-1) and programmed death-ligand 1 (PDL-1), has achieved a highly impressive milestone in the treatment of cancer. However, tumors can still achieve resistance to these therapies, in part by constitutively or adaptively upregulating PD-L1 expression. High PD-L1 expression can cause tumor cells to escape the host immune response by binding to its receptor PD-1, and thereby inactivating T-cell function. To help improve this situation, we propose a novel, rational combination therapy aimed at overcoming resistance by down-regulating PD-L1 expression and by improving the therapeutic efficacy through increasing T cell proliferation and enhancing immune cell function. We propose enhancing the therapeutic efficacy of anti-PD-1 by targeting of cyclin dependent kinase 5 (CDK5), a highly expressed kinase in most cancers. In a pilot study, we found that the CDK inhibitor, Roscovitine, that potently targets CDK5, decreased PD-L1 expression in cancer cells and suppressed the lung tumor growth in vivo when combined with anti-PD-1, increasing the survival of the mice. Importantly, tumors did not relapse even after the treatment was discontinued, and also after re-challenging the mice with cancer cells, with no further treatment. We propose 1) to define the underlying mechanisms through which this combination treatment overcomes resistance to ICB, and 2) to test the therapeutic efficacy of combining anti PD-1 with Roscovitine in a different cancer model, providing new hope for improving ICB therapy.