Immunotherapy is becoming the standard of care for melanoma. However, resistance to therapy is a major problem. Previously, we showed that tumor-specific, cytotoxic CD4 T cells from tyrosinase-related protein 1 transgenic mice could overcome secondary resistance to recurring melanoma when anti-programmed cell death 1 ligand (PD-L1) checkpoint blockade was combined with either anti-lymphocyte-activated gene 3 (LAG-3) Abs or depletion of tumor-specific regulatory T (T) cells. In this study, we show that PD-L1 expressed by the host, not B16 melanoma, plays a major role in the early stages of exhaustion or primary resistance. We observed durable regression of melanoma in tumor-bearing PD-L1RAG mice with transfer of naive tumor-specific CD4 T cells. However, exhausted tumor-specific CD4 T cells, which included tumor-specific T cells, failed to maintain durable regression of tumors in PD-L1RAG mice unless tumor-specific T cells were eliminated, showing nonredundant pathways of resistance to immunotherapy were present. Translating these findings to a clinically relevant model of cancer immunotherapy, we unexpectedly showed that anti-PD-L1 checkpoint blockade mildly improved immunotherapy with tumor-specific CD4 T cells and irradiation in wild-type mice. Instead, anti-LAG-3 checkpoint blockade, in combination with tumor-specific CD4 T cells and irradiation, overcame primary resistance and treated established tumors resulting in fewer recurrences. Because LAG-3 negatively regulates effector T cell function and activates T cells, LAG-3 blockade may be more beneficial in overcoming primary resistance in combination immunotherapies using adoptive cellular therapy and irradiation than blockade of PD-L1.
The innate and adaptive immune systems have evolved together to fight infection and cancerous tissues. The innate immune system emerges first with the adaptive immune system following, both ostensibly being bridged by dendritic cells (DC). Recently cells have emerged that possess characteristics of both innate and adaptive immune cell qualities, termed interferon-producing killer dendritic cells (IKDCs). These cells have an indistinct origin that is not well understood. They appear to have more NK cell attributes than DC but purportedly can regulate the immune system similar to immunoregulatory NK cells. Because of this, they have been renamed pre-mNK cells (pre-mature NK cells). We argue in this commentary that pre-mNK cells may contribute to cancer recurrence.
Our B16 melanoma mouse model, in which ~50% of mice receiving adoptive cellular therapy with cytolytic CD4+ T cells recognizing the tumor/self antigen tyrosinase protein 1 (TRP-1), exhibits tumor relapse following initial tumor regression. CD4+ T cells from tumor-bearing TRP-1 antigen knockout (tyrp1BwRAG-/-) transgenic mice, or tumor sensitized (t.s.) T cells, expressed low levels of the exhaustion marker PD-1 and were 15-25% Foxp3+. Due to this presensitization, B16 tumors recurred faster and more predictably in RAG-/- mice with t.s. CD4+ T cells than naïve TRP-1-specific CD4+ T cells. However, in RAG-/- mice lacking B7-H1 (i.e. PD-L1, the ligand for PD-1), relapses occurred more rarely and developed at slower rates following adoptive transfer of t.s. CD4+ T cells. When CD4+ T cells from mice bearing relapsing tumors, expressing high levels of PD-1 and Foxp3+, were transferred into either RAG-/- or B7-H1-/-RAG-/- mice, the treatment effect was completely abrogated. We previously reported that primary tumors required B7-H1 blockade or Treg depletion to be treated, and relapsing tumors required both treatments. Here we show that Treg cell depletion in B7-H1-/-RAG-/- mice partially restored treatment with fully exhausted CD4+ T cells and relapses took longer to occur. These data indicate that although multiple mechanisms are involved in tumor recurrence (Treg cells and PD-1), the expression of B7-H1 in the host rather than the tumor plays a major role in B16 melanoma relapse.
A major hurdle for cancer immunotherapy is the ability of tumors to inhibit anti-tumor immune responses. CD39 and CD73 are ectonucleotidases that promote the generation of extracellular adenosine from ATP. In light of the ability of adenosine to inhibit T cell responses by activating the adenosine A2a receptor (A2aR) we wanted to explore the expression of these two molecules on the surface of cancer cells. We investigated CD39 and CD73 expression and function utilizing murine and human tissues. In vitro studies revealed that Murine Lewis Lung Carcinoma cells did not express ectonucleotidases. However, upregulation of CD39 was found in vivo at multiple time points after injection into C57BL/6 mice. This expression was not T or B cell mediated as injection into RAG knockout mice produced the same expression patterns. Interestingly, characterization of multiple human lung cancer cells lines in vitro revealed near universal expression of CD73 and no CD39 expression. To determine if the upregulation of adenosine could have consequences in vivo, we injected Lewis lung carcinoma cells into A2aR knock out mice or wild-type mice treated with an adenosine receptor antagonist. In both cases improvements in tumor free and overall survival were observed. Overall our data suggests that CD39 and CD73 expression on the surface of lung cancer cells may contribute to their resistance to immunotherapy and that successful immunotherapy in lung cancer might include A2aR antagonists.
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