Tumor associated macrophages TAMs one of the limiting
Tumor-associated macrophages (TAMs)—one of the limiting factors in anti-tumor immunity—are associated with the poor clinical outcome in most carcinomas, owing to their potential to promote angiogenesis and local invasion, increase the metastasis of tumor cells, and inhibit the anti-tumor immunity.11, 12 Macrophages are highly dependent on the CSF-1 (colony-stimulating factor 1)/CSF-1R (CSF-1 receptor) pathway for survival and differentiation in most tissues. Therapeutic disruption of the CSF-1/CSF-1R pathway is of significant interest, as CSF-1 is highly expressed in several tumors. Certain CSF-1R inhibitors (e.g., PLX3397) were shown to delay tumor growth in certain cancers.14, 15
Low T cell infiltration in most tumors is another limitation for poor outcomes of immunotherapy. Previous studies have indicated increased T cell infiltration to be an indispensable predictive biomarker for better prognosis.16, 17 Hence, therapies to increase T cell infiltration would theoretically exhibit a synergetic effect with anti-PD-1 immunotherapy. Oncolytic virotherapy is a potential approach to increase T cell infiltration of tumor due to its advantages to selectively infect and kill tumor cells.18, 19 Oncolytic viruses (OVs) can lyse tumor leukotriene receptor antagonist directly and release tumor-associated antigens, which are presented by antigen-presenting cells to activate host anti-tumor immunity. Thus, OVs provide an ideal means to reverse the immunosuppressive tumor microenvironment and render tumors sensitive to the immune checkpoint blockade.
Although, a series of combination strategies has been tested in preclinical models and clinical settings, including combination with chemotherapy, radiotherapy, targeted therapy, and immunotherapy,22, 23, 24, 25 effective and rational combination approaches need to be explored to confer better therapeutic effects. Here we provide evidence that significant effects can be achieved by simultaneously combining a CSF-1R inhibitor (PLX3397) with OVs and anti-PD-1 antibody and this combination strategy could potentially overcome the limitations of low T cell infiltration and immunosuppression of TAMs and PD-1. This strategy might greatly improve the therapeutic efficacy of anti-PD-1 immunotherapy in colon cancer, the responses to which remain clinically limited. From the present investigation, we have proposed a novel combination strategy for improving the effects of immunotherapy in cancer patients.
Discussion Recent years have seen enormous breakthroughs in the field of cancer immunotherapy based on the successful development of immune checkpoint blockade.1, 23 However, not all the cancer types effectively respond to immune checkpoint blockade, including colon cancer.6, 8, 33 In our study, the effect of single treatment of anti-PD-1 antibody, PLX3397, or OVs was poor in mouse colon cancer. Accumulating evidence has now clarified that many factors operating within the tumor microenvironment contribute to the unsatisfactory outcomes of immunotherapy, which includes the recruitment of TAMs, MDSC, and Tregs and low T cell infiltration into the tumor. Similar findings were reported in our study. These factors work together to suppress the effects of anti-PD-1. The therapeutic outcomes were greatly improved by a triple combination of CSF-1R inhibitor, OVs, and anti-PD-1. It is clear that TAMs play a pivotal role in tumor progression and resistance to the PD-1 blockade,11, 34, 35 and they are tightly associated with poor prognosis.36, 37, 38 In our study, TAMs were highly enriched within the tumor in both mouse colon cancers and human colon cancer tissues, expressing the M2 phenotype marker CD206, which indicates the immunosuppressive functions of TAMs. Our findings suggest that targeting TAMs with PLX3397 (CSF-1R inhibitor) could effectively reduce TAMs and their mediated immunosuppression. These immune modulations induced by PLX3397 remarkably boosted the anti-PD-1 therapy, and the combination of PLX3397 and anti-PD-1 exhibited more effective tumor control. The therapeutic effects of PLX3397 alone were poor, similar to previous reports, which demonstrated that the therapeutic effects achieved by targeting the CSF-1/CSF-1R pathway alone with inhibitors or antibodies are limited in animal models and human cancers.39, 40 To date, objective responses for single-agent treatment have been achieved in patients with diffuse-type giant cell tumors. We propose that this limited efficacy is partly due to the alternative mechanisms that support tumor progression. Previous reports also demonstrated that the therapeutic effects were significantly augmented upon combining CSF-1R inhibitor with chemotherapy or immune checkpoint blockade.14, 41, 42