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S Tab 1: The application order of the pretreatment and staining steps, including epitope retrieval (ER), peroxidase and protein blocking, primary and secondary antibodies, and the Tyramide Signal Amplification (TSA).

Supplementary Figure Legends

Supplementary Figures 1-3: Representative images of stained lesions

S. Tab 2: Univariate models (batch adjusted only)

S. Tab 3: Histologic type analysis

Supplemental Figure 5. Confirmation of gut microbiota depletion.

Supplementary Figure 1. Basic functional characterization of B10G5 antibody. Supplementary Figure 2. Changes in serum levels of cytokines and chemokines with depletion of lymphocyte subsets during B10G5 therapy. Supplementary Figure 3. Anti-sMIC mAb B10G5 therapy significantly increase homeostatic proliferation of adoptively transferred NK cells. Supplementary Figure 4. B10G5 therapy did not impact CD4 T cell homeostasis but increased T-bet expression. Supplementary Figure S5. Undetectable endogenous SV40TAg epitope I-specific CD8 T cells shown by lack of positive staining by H-2Db-restrcited TAg epitope I-specific tetramer (Db/I-Tetramer). Supplementary Figure 6. Anti-sMIC mAb B10G5 therapy inhibits the growth of transplantable TRAMP-sMICB tumors. Supplementary Figure 7. Anti-sMIC therapy enhanced antigen-specific CD8 T cell responses in the transplantable TRAMP-C2-sMICB-OVA tumor model. Supplementary Figure 8. Therapeutic effect of B10G5 against well-differentiated TRAMP/MICB tumors. Supplementary Figure S9. Representative flow cytometry analyses demonstrating that depletion of NK cells during B10G5 therapy impairs CD4 T cell Th1 responses.

Supplementary Materials and Methods

Supplemental Figure 6. Characterization of the potent clinical-grade IDO enzyme inhibitor, BGB-7204.

Supplemental Figure 1. Inclusion and exclusion criteria for the analysis of human subjects diagnosed with glioblastoma (GBM).

Supplemental Figure 7. Bioluminescent imaging.

Purpose: The human tumor-derived soluble MHC I-chain–related molecule (sMIC) is highly immune suppressive in cancer patients and correlates with poor prognosis. However, the therapeutic effect of targeting sMIC has not been determined, due to the limitation that mice do not express homologs of human MIC. This study is to evaluate the therapeutic effect of a monoclonal antibody (mAb) targeting sMIC in a clinically relevant transgenic animal model.Experimental Design: We treated the engineered MIC-expressing “humanized” TRAMP/MIC bitransgenic mice at advanced disease stages with a sMIC-neutralizing nonblocking anti-MIC mAb and assessed the therapeutic efficacy and associated mechanisms.Results: A sMIC-neutralizing nonblocking anti-MIC mAb effectively induced regression of primary tumors and eliminated metastasis without inducing systemic toxicity. The therapeutic effect is conferred by revamping endogenous antitumor immune responses, exemplified by restoring natural killer (NK) cell homeostasis and function, enhancing susceptibility of MIC+-tumor cells to NK cell killing, reviving and sustaining antigen-specific CD8 T-cell responses, augmenting CD4 T cells to Th1 responses, priming dendritic cells for antigen presentation, and remodeling tumor microenvironment to be more immune reactive.Conclusions: Therapy with a sMIC-neutralizing nonblocking anti-MIC mAb can effectuate antitumor immune responses against advanced MIC+ tumors. Our study provided strong rationale for translating sMIC-neutralizing therapeutic mAb into clinics, either alone or in combination with current ongoing standard immunotherapies. Clin Cancer Res; 21(21); 4819–30. ©2015 AACR.

Supplemental Figure 2. Glioblastoma patient overall survival.

Purpose:Wild-type isocitrate dehydrogenase–expressing glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median age at diagnosis of ≥65 years. It accounts for approximately 90% of all GBMs and has a median overall survival (OS) of Experimental Design:(i) Clinical data: GBM patient datasets from The Cancer Genome Atlas, Northwestern Medicine Enterprise Data Warehouse, and clinical studies evaluating ICB were stratified by age and compared for OS. (ii) Animal models: young, middle-aged, and older adult wild-type and indoleamine 2,3 dioxygenase (IDO)-knockout syngeneic mice were intracranially engrafted with CT-2A or GL261 glioma cell lines and treated with or without CTLA-4/PD-L1 mAbs, or radiation, anti–PD-1 mAb, and/or a pharmacologic IDO enzyme inhibitor.Results:Advanced age was associated with decreased GBM patient survival regardless of treatment with ICB. The advanced age–associated increase of brain IDO expression was linked to the suppression of immunotherapeutic efficacy and was not reversed by IDO enzyme inhibitor treatment.Conclusions:Immunosuppression increases in the brain during advanced age and inhibits antiglioma immunity in older adults. Going forward, it will be important to fully understand the factors and mechanisms in the elderly brain that contribute to the decreased survival of older patients with GBM during treatment with ICB.

Supplemental Figure 4. Confirmatory analysis of T cell depletion method.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with cancer. Here, we developed and characterized proteolysis targeting chimeras (PROTACs) that degrade the IDO1 protein. IDO1-PROTACs were tested for their effects on IDO1 enzyme and non-enzyme activities. After screening a library of IDO1-PROTAC derivatives, a compound was identified that potently degraded the IDO1 protein through cereblon-mediated proteasomal degradation. The IDO1-PROTAC: (i) inhibited IDO1 enzyme activity and IDO1-mediated NF-κB phosphorylation in cultured human glioblastoma (GBM) cells, (ii) degraded the IDO1 protein within intracranial brain tumors in vivo, and (iii) mediated a survival benefit in mice with well-established brain tumors. This study identified and characterized a new IDO1 protein degrader with therapeutic potential for patients with glioblastoma.

Purpose: Glioblastoma (GBM) is an incurable primary brain tumor that has not benefited from immunotherapy to date. More than 90% of GBM expresses the tryptophan (Trp) metabolic enzyme, indoleamine 2,3-dioxygenase 1 (IDO). This observation supported the historical hypothesis that IDO suppresses the antitumor immune response solely through a mechanism that requires intratumoral Trp depletion. However, recent findings led us to investigate the alternative hypothesis that IDO suppresses the anti-GBM immune response independent of its association with Trp metabolism. Experimental Design: IDO-deficient GBM cell lines reconstituted with IDO wild-type or IDO enzyme–null cDNA were created and validated in vitro and in vivo. Microarray analysis was conducted to search for genes that IDO regulates, followed by the analysis of human GBM cell lines, patient GBM and plasma, and The Cancer Genome Atlas (TCGA) database. Ex vivo cell coculture assays, syngeneic and humanized mouse GBM models, were used to test the alternative hypothesis. Results: Nonenzymic tumor cell IDO activity decreased the survival of experimental animals and increased the expression of complement factor H (CFH) and its isoform, factor H like protein 1 (FHL-1) in human GBM. Tumor cell IDO increased CFH and FHL-1 expression independent of Trp metabolism. Increased intratumoral CFH and FHL-1 levels were associated with poorer survival among patients with glioma. Similar to IDO effects, GBM cell FHL-1 expression increased intratumoral regulatory T cells (Treg) and myeloid-derived suppressor cells while it decreased overall survival in mice with GBM. Conclusions: Our study reveals a nonmetabolic IDO-mediated enhancement of CFH expression and provides a new therapeutic target for patients with GBM.

Objective We evaluate data agreement between an electronic health record (EHR) sample abstracted by automated characterization with a standard abstracted by manual review. Study Design and Setting We obtain data for an epidemiology cohort study using standard manual abstraction of the EHR and automated identification of the same patients using a structured algorithm to query the EHR. Summary measures of agreement (e.g., Cohen’s kappa) are reported for 12 variables commonly used in epidemiological studies. Results Best agreement between abstraction methods is observed among demographic characteristics such as age, sex, and race, and for positive history of disease. Poor agreement is found in missing data and negative history, suggesting potential impact for researchers using automated EHR characterization. EHR data quality depends upon providers, who may be influenced by both institutional and federal government documentation guidelines. Conclusion Automated EHR abstraction discrepancies may decrease power and increase bias; therefore, caution is warranted when selecting variables from EHRs for epidemiological study using an automated characterization approach. Validation of automated methods must also continue to advance in sophistication with other technologies, such as machine learning and natural language processing, to extract non-structured data from the EHR, for application to EHR characterization for clinical epidemiology.

Harnessing natural killer (NK) cell activity, either endogenous NK or NK-cell-based therapy, is in the forefront development for many tumor types. There are compelling clinical evidence demonstrating the significant relevance of loss of NK cell activity with prostate cancer (PCa) disease progression to the lethal phenotype, metastatic castration-resistant PCa (mCRPC). Given that mCRPC is generally regarded as a “cold” tumor and has only elicited marginal response to immune checkpoint blockade therapy to revive CD8 T cell activity, NK cell targeted therapy may present a viable opportunity not only to directly target mCRPC and also to “fire up” the cold mCRPC tumor. However, current efforts on harnessing NK cell activity for treating mCRPC is very limited with only one open NK-cell-based clinical trial. This minireview will present the clinical significance of NK cell activity in controlling metastatic PCa and provide perspectives on harnessing NK cell activity for treating mCRPC.

Background Melanoma patients who have detectable serum soluble NKG2D ligands either at the baseline or post-treatment of PD1/PDL1 blockade exhibit poor overall survival. Among families of soluble human NKG2D ligands, the soluble human MHC I chain-related molecule (sMIC) was found to be elevated in melanoma patients and mostly associated with poor response to PD1/PDL1 blockade therapy. Methods In this study, we aim to investigate whether co-targeting tumor-released sMIC enhances the therapeutic outcome of PD1/PDL1 blockade therapy for melanoma. We implanted sMIC-expressing B16F10 melanoma tumors into syngeneic host and evaluated therapeutic efficacy of anti-sMIC antibody and anti-PDL1 antibody combination therapy in comparison with monotherapy. We analyzed associated effector mechanism. We also assessed sMIC/MIC prevalence in metastatic human melanoma tumors. Results We found that the combination therapy of the anti-PDL1 antibody with an antibody targeting sMIC significantly improved animal survival as compared to monotherapies and that the effect of combination therapy depends significantly on NK cells. We show that combination therapy significantly increased IL-2Rα (CD25) on NK cells which sensitizes NK cells to low dose IL-2 for survival. We demonstrate that sMIC negatively reprograms gene expression related to NK cell homeostatic survival and proliferation and that antibody clearing sMIC reverses the effect of sMIC and reprograms NK cell for survival. We further show that sMIC/MIC is abundantly present in metastatic human melanoma tumors. Conclusions Our findings provide a pre-clinical proof-of-concept and a new mechanistic understanding to underscore the significance of antibody targeting sMIC to improve therapeutic efficacy of anti-PD1/PDL1 antibody for MIC/sMIC+ metastatic melanoma patients.

Natural Killer (NK) cell dysfunction is associated with poorer clinical outcome in cancer patients. What regulates NK cell dysfunction in tumor microenvironment is not well understood. Here, we demonstrate that the human tumor-derived NKG2D ligand soluble MIC (sMIC) reprograms NK cell to secrete pro-tumorigenic cytokines with diminished cytotoxicity and polyfunctional potential. Antibody clearing sMIC restores NK cell to a normal cytotoxic effector functional state. We discovered that sMIC selectively activates the CBM-signalosome inflammatory pathways in NK cells. Conversely, tumor cell membrane-bound MIC (mMIC) stimulates NK cell cytotoxicity through activating PLC2γ2/SLP-76/Vav1 pathway. Ultimately, antibody targeting sMIC effectuated the in vivo anti-tumor effect of adoptively transferred NK cells. Our findings uncover an unrecognized mechanism that could instruct NK cell to a dysfunctional state in response to cues in the tumor microenvironment. Our findings provide a rationale for co-targeting sMIC to enhance the efficacy of the ongoing NK cell-based cancer immunotherapy., Dhar et al used primary human and mouse natural killer (NK) cells to demonstrate that tumor-derived NKG2D ligand soluble MIC (sMIC) can reprogram the NK cells to secrete pro-tumorigenic cytokines with diminished cytotoxicity and polyfunctional potential. Their study provides a rationale for co-targeting sMIC in order to enhance current NK cell-based cancer immunotherapies.

Black men die more often of prostate cancer yet, interestingly, may derive greater survival benefits from immune-based treatment with sipuleucel-T. Since no signatures of immune-responsiveness exist for prostate cancer, we explored race-based immune-profiles to identify vulnerabilities. Here we show in multiple independent cohorts comprised of over 1,300 patient samples annotated with either self-identified race or genetic ancestry, prostate tumors from Black men or men of African ancestry have increases in plasma cell infiltrate and augmented markers of NK cell activity and IgG expression. These findings are associated with improved recurrence-free survival following surgery and nominate plasma cells as drivers of prostate cancer immune-responsiveness., A recent report suggested Black men with prostate cancer were more responsive to immunotherapy. Here, the authors analysed prostate cancer gene expression profiles and show tumours from Black men and men with African ancestry have an increased proportion of plasma cells compared to those of White men and this correlates with improved outcome following treatment.

Background Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDHwt GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDHwt GBM have a median age of diagnosis at 68–70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM. Methods The Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship. Results Despite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve. Conclusions Based upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDHwt GBM patient outcomes.

Background & aims Tumor-infiltrating neutrophils (polymorphonuclear neutrophils [PMNs]) are a prominent feature of colorectal cancer (CRC), where they can promote cytotoxicity or exacerbate disease outcomes. We recently showed that in acute colon injury, PMNs can increase DNA double-strand break (DSB) burden and promote genomic instability via microRNA-dependent inhibition of homologous recombination (HR) repair. In this study, we aimed to establish whether in inflamed colon, neutrophils shape the DSB-repair responses to impact CRC progression and sensitivity/resistance to DNA-repair targeted therapy. Methods Human sporadic CRC biopsies, The Cancer Genome Atlas gene expression analyses, tumor xenografts, and murine CRC models, as well as small-molecule inhibition of key DSB-repair factors were leveraged to investigate changes in the DSB-repair landscape and identify unique CRC responses with/without tumor infiltration by PMNs. Results We reveal that neutrophils exert a functional dualism in cancer cells, driving temporal modulation of the DNA damage landscape and resolution of DSBs. PMNs were found to promote HR deficiency in low-grade CRC by miR-155-dependent downregulation of RAD51, thus attenuating tumor growth. However, neutrophil-mediated genotoxicity due to accumulation of DSBs led to the induction of non-homologous end-joining (NHEJ), allowing for survival and growth of advanced CRC. Our findings identified a PMN-induced HR-deficient CRC phenotype, featuring low RAD51 and low Ku70 levels, rendering it susceptible to synthetic lethality induced by clinically approved PARP1 inhibitor Olaparib. We further identified a distinct PMN-induced HR-deficient CRC phenotype, featuring high Ku70 and heightened NHEJ, which can be therapeutically targeted by specific inhibition of NHEJ. Conclusions Our work delineates 2 mechanism-based translatable therapeutic interventions in sporadic CRC.

BackgroundInflammatory bowel disease (IBD) has been implicated as a risk factor for prostate cancer, however, the mechanism of how IBD leads to prostate tumorigenesis is not known. Here, we investigated whether chronic intestinal inflammation leads to pro-inflammatory changes associated with tumorigenesis in the prostate.MethodsUsing clinical samples of men with IBD who underwent prostatectomy, we analyzed whether prostate tumors had differences in lymphocyte infiltrate compared to non-IBD controls. In a mouse model of chemically-induced intestinal inflammation, we investigated whether chronic intestinal inflammation could be transferred to the wild-type mouse prostate. In addition, mouse prostates were evaluated for activation of pro-oncogenic signaling and genomic instability.ResultsA higher proportion of men with IBD had T and B lymphocyte infiltration within prostate tumors. Mice with chronic colitis showed significant increases in prostatic CD45 + leukocyte infiltration and elevation of three pro-inflammatory cytokines-TIMP-1, CCL5, and CXCL1 and activation of AKT and NF-kB signaling pathways. Lastly, mice with chronic colitis had greater prostatic oxidative stress/DNA damage, and prostate epithelial cells had undergone cell cycle arrest.ConclusionsThese data suggest chronic intestinal inflammation is associated with an inflammatory-rich, pro-tumorigenic prostatic phenotype which may explain how gut inflammation fosters prostate cancer development in men with IBD.

Immune responses vary in colorectal cancers, which strongly influence prognosis. However, little is known about the variance in immune response within preinvasive lesions. The study aims to investigate how the immune contexture differs by clinicopathologic features (location, histology, dysplasia) associated with progression and recurrence in early carcinogenesis. We performed a cross-sectional study using preinvasive lesions from the surgical pathology laboratory at the Medical University of South Carolina. We stained the tissues with immunofluorescence antibodies, then scanned and analyzed expression using automated image analysis software. We stained CD117 as a marker of mast cells, CD4/RORC to indicate Th17 cells, MICA/B as a marker of NK-cell ligands, and also used antibodies directed against cytokines IL6, IL17A, and IFNγ. We used negative binomial regression analysis to compare analyte density counts by location, histology, degree of dysplasia adjusted for age, sex, race, and batch. All immune markers studied (except IL17a) had significantly higher density counts in the proximal colon than distal colon and rectum. Increases in villous histology were associated with significant decreases in immune responses for IL6, IL17a, NK ligand, and mast cells. No differences were observed in lesions with low- and high-grade dysplasia, except in mast cells. The lesions of the proximal colon were rich in immune infiltrate, paralleling the responses observed in normal mucosa and invasive disease. The diminishing immune response with increasing villous histology suggests an immunologically suppressive tumor environment. Our findings highlight the heterogeneity of the immune responses in preinvasive lesions, which may have implications for prevention strategies. Prevention Relevance: Our study is focused on immune infiltrate expression in preinvasive colorectal lesions; our results suggest important differences by clinicopathologic features that have implications for immune prevention research.

BackgroundInflammatory bowel disease (IBD) is an established risk factor for colorectal cancer. Recent reports suggesting IBD is also a risk factor for prostate cancer (PC) require further investigation.ObjectiveTo test the association between IBD with incident PC.Design, setting, and participantsWe studied 218,084 men in the population-based UK Biobank cohort, aged 40-69 at study entry between 2006 and 2010, with follow-up through mid-2015.Outcome measurements and statistical analysisWe assessed the association between IBD and subsequent PC using multivariable Cox regression analyses, adjusting for age at assessment, ethnic group, UK region, smoking status, alcohol drinking frequency, body mass index, Townsend Deprivation Index, family history of prostate cancer, and previous prostate-specific antigen testing.Results and limitationsMean age at study entry was 56 years, 94% of the men were white, and 1.1% (n=2,311) had a diagnosis of IBD. After a median follow-up of 78 months, men with IBD had an increased risk of PC (adjusted hazards ratio [aHR] = 1.31, 95% Confidence interval [CI] = 1.03-1.67, p = 0.029). Separately analyzing the IBD subtypes of ulcerative colitis (UC) and Crohn’s disease (CD), the association with PC was only among men with the former (UC; aHR = 1.47, 95% CI = 1.11-1.95, p=0.0070), and not the latter (CD; aHR 1.06, 95% CI = 0.63-1.80, p = 0.82). Results are limited by lack of data on frequency of health care interactions.ConclusionsIn a large-scale, prospective cohort study, we detected an association between IBD, and UC specifically, with incident PC diagnosis.Patient summaryThis study of over 200,000 men in the UK suggests that men with inflammatory bowel disease may be at a higher risk of prostate cancer than the general population.

Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Different from events required for T cell activation, NK cell activation is governed by the interaction of NK receptors with target cells, independent of antigen processing and presentation. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. In this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives.

CD73 (ecto-5'-nucleotidase) is a novel immunoinhibitory protein that plays a key role for tumor growth and metastasis. Its main function is to convert extracellular ATP to immunosuppressive adenosine in concert with CD39 in normal tissues to limit excessive immune response. However, tumors take advantage of the CD73-mediated adenosinergic mechanism to protect them from immune attack. In particular, inducible expression of CD73 along with other adenosinergic molecules on both cancer cells and host cells sustains immunosuppressive tumor microenvironment by affecting multiple aspects of the immune response. Owing to its multifaceted capacity to tumor promotion as an emerging immune checkpoint, CD73 is an ideal therapeutic target for cancer treatment especially in combination with conventional therapy and/or other immune checkpoint inhibitors. In this review, we will discuss the roles of CD73 on tumor and immune cells and will highlight the therapeutic value of CD73 for combination therapy.

INTRODUCTION AND OBJECTIVE:Inflammatory bowel disease (IBD) increases one’s risk of colorectal cancer (CRC). Recent data implicating IBD as a risk factor for prostate cancer (PC) requires external ...

INTRODUCTION AND OBJECTIVE:Recent epidemiological data has implicated inflammatory bowel disease (IBD) as a risk factor for clinically significant prostate cancer (PC). One key driver of malignant ...

Inflammatory bowel disease (IBD) is an established risk factor for colorectal cancer. Recent reports suggesting IBD is also a risk factor for prostate cancer (PC) require further investigation. We studied 218 084 men in the population-based UK Biobank cohort, aged 40 to 69 at study entry between 2006 and 2010, with follow-up through mid-2015. We assessed the association between IBD and subsequent PC using multivariable Cox regression analyses, adjusting for age at assessment, ethnic group, UK region, smoking status, alcohol drinking frequency, body mass index, Townsend Deprivation Index, family history of PC and previous prostate-specific antigen testing. Mean age at study entry was 56 years, 94% of the men were white, and 1.1% (n = 2311) had a diagnosis of IBD. After a median follow-up of 78 months, men with IBD had an increased risk of PC (adjusted hazard ratio [aHR] = 1.31, 95% confidence interval [CI] = 1.03-1.67, P = .029). The association with PC was only among men with the ulcerative colitis (UC; aHR = 1.47, 95% CI = 1.11-1.95, P = .0070), and not Crohn's disease (aHR 1.06, 95% CI = 0.63-1.80, P = .82). Results are limited by lack of data on frequency of health care interactions. In a large-scale, prospective cohort study, we detected an association between IBD, and UC specifically, with incident PC diagnosis.

Purpose: Wild-type isocitrate dehydrogenase–expressing glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median age at diagnosis of ≥65 years. It accounts for approximately 90% of all GBMs and has a median overall survival (OS) of Experimental Design: (i) Clinical data: GBM patient datasets from The Cancer Genome Atlas, Northwestern Medicine Enterprise Data Warehouse, and clinical studies evaluating ICB were stratified by age and compared for OS. (ii) Animal models: young, middle-aged, and older adult wild-type and indoleamine 2,3 dioxygenase (IDO)-knockout syngeneic mice were intracranially engrafted with CT-2A or GL261 glioma cell lines and treated with or without CTLA-4/PD-L1 mAbs, or radiation, anti–PD-1 mAb, and/or a pharmacologic IDO enzyme inhibitor. Results: Advanced age was associated with decreased GBM patient survival regardless of treatment with ICB. The advanced age–associated increase of brain IDO expression was linked to the suppression of immunotherapeutic efficacy and was not reversed by IDO enzyme inhibitor treatment. Conclusions: Immunosuppression increases in the brain during advanced age and inhibits antiglioma immunity in older adults. Going forward, it will be important to fully understand the factors and mechanisms in the elderly brain that contribute to the decreased survival of older patients with GBM during treatment with ICB.

Background: Compared with Caucasian Americans (CAs), African Americans (AAs) with colorectal cancer have poorer survival, especially younger-age patients. A robust lymphocytic reaction within colorectal cancers is strongly associated with better survival, but whether immune response impacts the disparity in colorectal cancer survival is unknown. Methods: The study population was comprised of 211 histologically confirmed colorectal cancers at the Medical University of South Carolina (Charleston, SC; 159 CAs and 52 AAs) diagnosed between Jan 01, 2000, and June 30, 2013. We constructed a lymphocyte score based on blinded pathologic assessment of the four different types of lymphocytic reactions. Cox proportional hazards regression was used to evaluate the association between the lymphocyte score and risk of death by race. Results: Colorectal cancers in AAs (vs. CAs) had a stronger lymphocytic reaction at diagnosis. A high lymphocyte score (vs. the lowest) was associated with better survival in AAs [HR 0.19; 95% confidence interval (CI), 0.04–0.99] and CAs (HR 0.47; 95% CI, 0.15–1.45). AAs with no lymphocytic reaction (vs. other categories) had poor survival HR 4.48 (1.58–12.7) whereas no difference was observed in CAs. The risk of death in AAs (vs. CA) was more pronounced in younger patients (HR 2.92; 95% CI, 1.18–7.22) compared with older (HR 1.20; 95% CI, 0.54–2.67), especially those with lymphocytic poor colorectal cancers. Conclusions: The lymphocytic reaction in tumor impacted the racial disparity in survival. Impact: Our results confirm the importance of the lymphocytic score on survival and highlight the need to fully characterize the immune environment of colorectal cancers by race. Cancer Epidemiol Biomarkers Prev; 27(7); 755–61. ©2018 AACR.