Lung cancer is a leading cause of cancer-related death worldwide. Many standardized treatment options such as surgery, radiation, chemotherapy, targeted therapy and recently developed immunotherapy have been established and implemented for decades. More than one half of patients are diagnosed as advanced lung cancer when present at hospital and patients with advanced non-small cell lung cancer (~85% of lung cancer incidence) have still suffered from limited treatment efficacy and poor prognosis. In order to develop new and more effective strategy in the clinical treatment of NSCLC, we have desired to find some new tumor associated antigens for drug development.
When our lab was set up in 2013, we have started to screen genes that encode secreting proteins and are highly expressed in the fresh tumor biopsies compared to the adjacent normal tissues of NSCLC patients. Interestingly, few genes had the higher mRNA levels in tumor than the adjacent normal tissues, among which CCL7 is one candidate. Although it has been reported that overexpression of CCL7 in tumor cells promotes tumorigenesis by facilitating tumor cell proliferation and metastasis or retains tumor growth by recruiting immune cells into tumors in exogenous mouse models, whether and how CCL7 is involved in primary NSCLC development in vivo are unclear.
In collaboration with Dr. Qian Chu at Tongji Hospital of Huazhong University of Science and Technology, we have found that high levels of CCL7 in the tumor biopsies are positively correlated with better overall survival of NSCLC patients. Interestingly, CCL7 is upregulated in the tumor-burdened lungs of KrasLSL-G12D/+Tp53fl/fl NSCLC mouse model in a JAK-STAT-dependent manner. By generating the CCL7IRES-ZsGreen mice, we have confirmed that CCL7 is barely expressed in various types of cells in the lungs of naive mice and is upregulated in alveolar macrophages, tumor cells and endothelial cells but not in conventional dendritic cells (cDCs), NK cells, T cells or B cells in the lungs of KrasLSL-G12D/+Tp53fl/flCcl7IRES-ZsGreen mice after tumor induction.
We next investigated the role of CCL7 in NSCLC development in KrasLSL-G12D/+Tp53fl/fl mice. Knockout of CCL7 significantly impairs the infiltration of cDC1 and the expansion of T cells in tumor-burdened lungs and bronchial draining lymph nodes without affecting the differentiation or activation of cDC1 or T cells. Conversely, intranasal injection of CCL7 promotes the infiltration of cDC1 and T cells in tumor-burdened lungs and depletion of DCs abrogates the effects of CCL7-mediated anti-tumor activity, suggesting critical roles of CCL7-cDC1-T cell axis in antitumor immunity.
Because the efficacy of immunocheckpoint blockade (ICB) therapies is closely related with tumor-infiltrated lymphocytes, the above observations inspire us that CCL7 serves as an adjuvant in ICB of NSCLC by modulating the cDC1-T cell axis. Expectedly, combination of CCL7 with PD-1 antibodies achieve better efficacy than anti-PD-1 alone in treatment of KrasLSL-G12D/+Tp53fl/fl or KrasLSL-G12D/+Lkb1fl/fl NSCLC mouse models. These findings have at lease two indications: (1) combo of CCL7 and ICBs could improve the prognosis of NSCLC patients and (2) it should be very caution to treat cancer with inhibitors of CCL7 receptors CCR1/2/3.