The complement cascade is a part of the innate immune system that acts primarily to remove pathogens and injured cells. However, complement activation is also peculiarly associated with tumor progression. Here we report mechanistic insights into this association in multiple immunocompetent orthotopic models of lung cancer. After tumor engraftment, we observed systemic activation of the complement cascade as reflected by elevated levels of the key regulator C3a. Notably, growth of primary tumors and metastases was both strongly inhibited in C3-deficient mice (C3 mice), with tumors undetectable in many subjects. Growth inhibition was associated with increased numbers of IFNγ/TNFα/IL10 CD4 and CD8 T cells. Immunodepletion of CD4 but not CD8 T cells in tumor-bearing subjects reversed the inhibitory effects of C3 deletion. Similarly, antagonists of the C3a or C5a receptors inhibited tumor growth. Investigations using multiple tumor cell lines in the orthotopic model suggested the involvement of a C3/C3 receptor autocrine signaling loop in regulating tumor growth. Overall, our findings offer functional evidence that complement activation serves as a critical immunomodulator in lung cancer progression, acting to drive immune escape via a C3/C5-dependent pathway. This provocative study suggests that inhibiting complement activation may heighten immunotherapeutic responses in lung cancer, offering findings with immediate implications, given the existing clinical availability of complement antagonists. .

The anaplastic lymphoma kinase (ALK) gene plays an important physiologic role in the development of the brain and can be oncogenically altered in several malignancies, including non-small-cell lung cancer (NSCLC) and anaplastic large cell lymphomas (ALCL). Most prevalent ALK alterations are chromosomal rearrangements resulting in fusion genes, as seen in ALCL and NSCLC. In other tumors, ALK copy-number gains and activating ALK mutations have been described. Dramatic and often prolonged responses are seen in patients with ALK alterations when treated with ALK inhibitors. Three of these—crizotinib, ceritinib, and alectinib—are now FDA approved for the treatment of metastatic NSCLC positive for ALK fusions. However, the emergence of resistance is universal. Newer ALK inhibitors and other targeting strategies are being developed to counteract the newly emergent mechanism(s) of ALK inhibitor resistance. This review outlines the recent developments in our understanding and treatment of tumors with ALK alterations.

Given recent evidence suggesting that the heat-labile enterotoxin (LT) provides a colonization advantage for enterotoxigenic Escherichia coli (ETEC) in vivo, we hypothesized that LT preconditions the host intestinal epithelium for ETEC adherence. To test this hypothesis, we used an in vitro model of ETEC adherence to examine the role of LT in promoting bacterium-host interactions. We present data demonstrating that elaboration of LT promotes a significant increase in E. coli adherence. This phenotype is primarily dependent on the inherent ADP-ribosylation activity of this toxin, with a secondary role observed for the receptor-binding LT-B subunit. Rp-3,5-cyclic AMP (cAMP), an inhibitor of protein kinase A, was sufficient to abrogate LT's ability to promote subsequent bacterial adherence. Increased adherence was not due to changes in the surface expression of the host receptor for the K88ac adhesin. Evidence is also presented for a role for bacterial sensing of host-derived cAMP in promoting adherence to host cells.

MHC class II (MHCII) expression is usually restricted to APC but can be expressed by cancer cells. We examined the effect of cancer cell-specific MHCII (csMHCII) expression in lung adenocarcinoma on T cell recruitment to tumors and response to anti-PD-1 therapy using two orthotopic immunocompetent murine models of non-small cell lung cancer: CMT167 (CMT) and Lewis lung carcinoma (LLC). We previously showed that CMT167 tumors are eradicated by anti-PD1 therapy, whereas LLC tumors are resistant. RNA sequencing analysis of cancer cells recovered from tumors revealed that csMHCII correlated with response to anti-PD1 therapy, with immunotherapy-sensitive CMT167 cells being csMHCII positive, whereas resistant LLC cells were csMHCII negative. To test the functional effects of csMHCII, MHCII expression was altered on the cancer cells through loss-and gain-offunction of CIITA, a master regulator of the MHCII pathway. Loss of CIITA in CMT167 decreased csMHCII and converted tumors from anti-PD-1 sensitive to anti-PD-1 resistant. This was associated with lower levels of Th1 cytokines, decreased T cell infiltration, increased B cell numbers, and decreased macrophage recruitment. Conversely, overexpression of CIITA in LLC cells resulted in csMHCII in vitro and in vivo. Enforced expression of CIITA increased T cell infiltration and sensitized tumors to anti-PD-1 therapy. csMHCII expression was also examined in a subset of surgically resected human lung adenocarcinomas by multispectral imaging, which provided a survival benefit and positively correlated with T cell infiltration. These studies demonstrate a functional role for csMHCII in regulating T cell infiltration and sensitivity to anti-PD-1.

Eicosanoids represent a family of active biolipids derived from arachidonic acid primarily through the action of cytosolic phospholipase A2-α. Three major downstream pathways have been defined: the cyclooxygenase (COX) pathway which produces prostaglandins and thromboxanes; the 5-lipoxygenase pathway (5-LO), which produces leukotrienes, lipoxins and hydroxyeicosatetraenoic acids, and the cytochrome P450 pathway which produces epoxygenated fatty acids. In general, these lipid mediators are released and act in an autocrine or paracrine fashion through binding to cell surface receptors. The pattern of eicosanoid production is cell specific, and is determined by cell-specific expression of downstream synthases. Increased eicosanoid production is associated with inflammation and a panel of specific inhibitors have been developed designated non-steroidal anti-inflammatory drugs. In cancer, eicosanoids are produced both by tumor cells as well as cells of the tumor microenvironment. Earlier studies demonstrated that prostaglandin E2, produced through the action of COX-2, promoted cancer cell proliferation and metastasis in multiple cancers. This resulted in the development of COX-2 inhibitors as potential therapeutic agents. However, cardiac toxicities associated with these agents limited their use as therapeutic agents. The advent of immunotherapy, especially the use of immune checkpoint inhibitors has revolutionized cancer treatment in multiple malignancies. However, the majority of patients do not respond to these agents as monotherapy, leading to intense investigation of other pathways mediating immunosuppression in order to develop rational combination therapies. Recent data have indicated that PGE2 has immunosuppressive activity, leading to renewed interest in targeting this pathway. However, little is known regarding the role of other eicosanoids in modulating the tumor microenvironment, and regulating anti-tumor immunity. This article reviews the role of eicosanoids in cancer, with a focus on their role in modulating the tumor microenvironment. While the role of PGE2 will be discussed, data implicating other eicosanoids, especially products produced through the lipoxygenase and cytochrome P450 pathway will be examined. The existence of small molecular inhibitors and activators of eicosanoid pathways such as specific receptor blockers make them attractive candidates for therapeutic trials, especially in combination with novel immunotherapies such as immune checkpoint inhibitors.