Jen, Jin

Although immune checkpoint inhibitors have resulted in durable clinical benefits in a subset of patients with advanced cancer, some patients who did not respond to initial anti–PD-1 therapy have been found to benefit from the addition of salvage chemotherapy. However, the mechanism responsible for the successful chemoimmunotherapy is not completely understood. Here we show that a subset of circulating CD8 + T cells expressing the chemokine receptor CX3CR1 are able to withstand the toxicity of chemotherapy and are increased in patients with metastatic melanoma who responded to chemoimmunotherapy (paclitaxel and carboplatin plus PD-1 blockade). These CX3CR1 + CD8 + T cells have effector memory phenotypes and the ability to efflux chemotherapy drugs via the ABCB1 transporter. In line with clinical observation, our preclinical models identified an optimal sequencing of chemoimmunotherapy that resulted in an increase of CX3CR1 + CD8 + T cells. Taken together, we found a subset of PD-1 therapy–responsive CD8 + T cells that were capable of withstanding chemotherapy and executing tumor rejection with their unique abilities of drug efflux (ABCB1), cytolytic activity (granzyme B and perforin), and migration to and retention (CX3CR1 and CD11a) at tumor sites. Future strategies to monitor and increase the frequency of CX3CR1 + CD8 + T cells may help to design effective chemoimmunotherapy to overcome cancer resistance to immune checkpoint blockade therapy.

Purpose To develop a genomic signature that predicts benefit from trastuzumab in human epidermal growth factor receptor 2–positive breast cancer. Patients and Methods DASL technology was used to quantify mRNA in samples from 1,282 patients enrolled onto the Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer (North Central Cancer Treatment Group N9831 [NCCTG-N9831]) adjuvant trastuzumab trial. Cox proportional hazard ratios (HRs), adjusted for significant clinicopathologic risk factors, were used to determine the association of each gene with relapse-free survival (RFS) for 433 patients who received chemotherapy alone (arm A) and 849 patients who received chemotherapy plus trastuzumab (arms B and C). Network and pathway analyses were used to identify key biologic processes linked to RFS. The signature was built by using a voting scheme. Results Network and functional ontology analyses suggested that increased RFS was linked to a subset of immune function genes. A voting scheme model was used to define immune gene enrichment based on the expression of any nine or more of 14 immune function genes at or above the 0.40 quantile for the population. This model was used to identify immune gene–enriched tumors in arm A and arms B and C. Immune gene enrichment was linked to increased RFS in arms B and C (HR, 0.35; 95% CI, 0.22 to 0.55; P < .001), whereas arm B and C patients who did not exhibit immune gene enrichment did not benefit from trastuzumab (HR, 0.89; 95% CI, 0.62 to 1.28; P = .53). Enriched immune function gene expression as defined by our predictive signature was not associated with increased RFS in arm A (HR, 0.90; 95% CI, 0.60 to 1.37; P = .64). Conclusion Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab.

Abstract In searching for a role for genetic variation in susceptibility to lung cancer, we postulated that miRNA modulating SNPs within smoking behavior associated genes, such as the nicotinic acetylcholine and dopamine receptor families, could modulate susceptibility to tobacco carcinogens and lung cancer risk. Bioinformatic analyses of these gene families identified 5 SNPs predicted to modulate a miRNA binding site. We assessed these SNPs in the National Cancer Institute-MD case-control study (European American [EA] & African Americans [AA] n=1,438). rs686 in DRD1 (dopamine receptor D1) was associated with a reduced risk of lung cancer after adjustment for age, gender and race (OR 0.63, 95% C.I. 0.47-0.85; P=0.002). As DRD1 mediates dopamine signaling following nicotine exposure, we reasoned that the rs686 variant associates with lung cancer risk via modulation of the nicotine reward pathway. However, adjustment for smoking both in terms of smoking status and pack-years did not significantly modulate the association (OR 0.57, 95% C.I. 0.40-0.81, P=0002). In addition, age at smoking initiation, pack-years of smoking and levels of urinary nicotine metabolites (cotinine and hydroxycotinine) did not vary across rs686 genotypes. Moreover, in an analysis of a never smoking cohort from Mayo Clinic, rs686 was also associated with a reduced risk of lung cancer (OR 0.77, 95% C.I. 0.62-0.97; P=0.027; n=629) (pooled analysis OR 0.61, 95% C.I. 0.47-0.78; P&lt;0.0001; n=2,067). Intriguingly, the association between rs686 and lung cancer risk was only observed in subjects exposed to tobacco smoke during childhood (EA smokers: [OR 0.63, 95% C.I. 0.45-0.88; P=0.007] EA never smokers [OR 0.64, 95% C.I. 0.49-0.85; P=0.002] AA smokers OR 0.31, 95% C.I. 0.11-0.89; P=0.029) (model adjusted as above and for education, adult-second-hand smoke exposure). To further explore a relationship between tobacco and DRD1, we exposed lung cancer cell lines to increasing doses of nicotine and observed a significant increase in DRD1 expression (P=0.009). As DRD1 lies within a CpG island, we are currently testing if this regulation occurs via epigenetic modulation of the DRD1 promoter. While a direct role for DRD1 in lung cancer has not previously been reported, a recent report linked DRD to the cancer stem cell hypothesis. Indeed, our work demonstrates that DRD1 is significantly upregulated in lung cells with cancer stem-like properties. Furthermore, miR-296, predicted to bind to variant rs686 allele, is increased in paired lung cancer tissues (P=0.0003), thus linking a decrease in DRD1 with reduced lung cancer risk. Collectively, our work suggests a novel lung cancer pathway whereby rs686 in DRD1 counteracts the increase in DRD1 imposed by exposure to tobacco smoke in both current and never smokers. Furthermore, it hints at a novel role for the dopamine receptor/signaling pathway in lung carcinogenesis. Citation Format: Brid M. Ryan, Ana I. Robles, Andrew C. McClary, Elise Bowman, Kirsi Vahakangas, Susan Olivo-Marston, Ping Yang, Jin Jen, Curtis C. Harris. Interaction between DRD1 and childhood exposure to environmental tobacco smoke modulates lung cancer risk in smokers and never smokers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4581. doi:10.1158/1538-7445.AM2013-4581