Sex disparities in the incidence and mortality of lung cancer have been observed since cancer statistics have been recorded. Social and economic differences contribute to sex disparities in lung cancer incidence and mortality, but evidence suggests that there are also underlying biological differences that contribute to the disparity. This review summarizes biological differences which could contribute to the sex disparity. Sex hormones and other biologically active molecules, tumor cell genetic differences, and differences in the immune system and its response to lung cancer are highlighted. How some of these differences contribute to disparities in the response to therapies, including cytotoxic, targeted, and immuno-therapies, is also discussed. We end the study with a discussion of our perceived future directions to identify the key biological differences which could contribute to sex disparities in lung cancer and how these differences could be therapeutically leveraged to personalize lung cancer treatment to the individual sexes.

Significance: Metastasis is a leading cause of breast cancer-associated death. MDA-9/Syntenin expression is elevated and contributes at multiple nodal points in the metastatic process. Inhibition of MDA-9/Syntenin using a pharmacological inhibitor (PDZ1i), which blocks protein–protein interactions, suppresses metastasis in syngeneic mouse and human xenograft models. PDZ1i therapy robustly constrains breast cancer metastasis in syngeneic animals by inhibiting tumor cell-derived interleukin-1β secretion through deactivation of STAT3 and reducing infiltration of immune suppressor cells in the metastatic niche. Enhanced antitumor immunity correlates with expansion of interferon-γ–expressing T cells and conversion of the immunosuppressive microenvironment into an immunostimulatory tumor environment. Collectively, our findings highlight the essential function of MDA-9/Syntenin in immune tolerance, documenting a promising therapeutic strategy selectively targeting breast cancer metastasis.

BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands

Genetic studies in fruit flies have implicated the chromatin remodeling complex nucleosome remodeling factor (NURF) in immunity, but it has yet to be studied in mammals. Here we show that its targeting in mice enhances antitumor immunity in two syngeneic models of cancer. NURF was disabled by silencing of bromodomain PHD-finger containing transcription factor (BPTF), the largest and essential subunit of NURF. We found that both CD8⁺ and CD4⁺ T cells were necessary for enhanced antitumor activity, with elevated numbers of activated CD8⁺ T cells observed in BPTF-deficient tumors. Enhanced cytolytic activity was observed for CD8⁺ T cells cocultured with BPTF-silenced cells. Similar effects were not produced with T-cell receptor transgenic CD8⁺ T cells, implicating the involvement of novel antigens. Accordingly, enhanced activity was observed for individual CD8⁺ T-cell clones from mice bearing BPTF-silenced tumors. Mechanistic investigations revealed that NURF directly regulated the expression of genes encoding immunoproteasome subunits Psmb8 and Psmb9 and the antigen transporter genes Tap1 and Tap2. The PSMB8 inhibitor ONX-0914 reversed the effects of BPTF ablation, consistent with a critical role for the immunoproteasome in improving tumor immunogenicity. Thus, NURF normally suppresses tumor antigenicity and its depletion improves antigen processing, CD8 T-cell cytotoxicity, and antitumor immunity, identifying NURF as a candidate therapeutic target to enhance antitumor immunity. Cancer Res; 76(21); 6183–92. ©2016 AACR.

Epigenetic regulators can modulate the effects of cancer therapeutics. To further these observations, we discovered that the bromodomain PHD finger transcription factor subunit (BPTF) of the nucleosome remodeling factor (NURF) promotes resistance to doxorubicin, etoposide, and paclitaxel in the 4T1 breast tumor cell line. BPTF functions in promoting resistance to doxorubicin and etoposide, but not paclitaxel, and may be selective to cancer cells, as a similar effect was not observed in embryonic stem cells. Sensitization to doxorubicin and etoposide with BPTF knockdown (KD) was associated with increased DNA damage, topoisomerase II (TOP2) crosslinking and autophagy; however, there was only a modest increase in apoptosis and no increase in senescence. Sensitization to doxorubicin was confirmed in vivo with the syngeneic 4T1 breast tumor model using both genetic and pharmacologic inhibition of BPTF. The effects of BPTF inhibition in vivo are autophagy dependent, based on genetic autophagy inhibition. Finally, treatment of 4T1, 66cl4, 4T07, MDA-MB-231, but not ER-positive 67NR and MCF7 breast cancer cells with the selective BPTF bromodomain inhibitor, AU1, recapitulates genetic BPTF inhibition, including in vitro sensitization to doxorubicin, increased TOP2-DNA crosslinks and DNA damage. Taken together, these studies demonstrate that BPTF provides resistance to the antitumor activity of TOP2 poisons, preventing the resolution of TOP2 crosslinking and associated autophagy. These studies suggest that BPTF can be targeted with small-molecule inhibitors to enhance the effectiveness of TOP2-targeted cancer chemotherapeutic drugs.Implications: These studies suggest NURF can be inhibited pharmacologically as a viable strategy to improve chemotherapy effectiveness.

Background/Objectives: Tumor cells exploit a variety of mechanisms to inhibit the immune response to lung cancer. The programmed cell death protein-1/programmed death-ligand-1 (PD-1/PD-L1) axis is frequently dysregulated in lung cancers with significant impacts on tumor growth. A sex difference has been observed in lung cancer progression and the response to PD-1/PD-L1 therapy, with the extent of benefits differing between men and women. The mechanism underlying these differences has not been fully established. Methods: In an attempt to better understand the nature of these differences, we searched the available literature for reports connecting sex specific bioactive molecules—including estrogens, progesterone, testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, leptin, and activin/inhibin—to sex differences in lung cancer and the response to PD-1/PDL-1 therapies. We then condensed this information to help generate testable hypotheses to explain the observed sex differences in lung cancer and its immunotherapies. Conclusions: From these efforts, we discovered potential roles for sex steroids, FSH, LH, prolactin, leptin, and activin/inhibin in both immune cell activity and cancer cell survival and in the response to PD-1/PD-L1 therapies.