Purpose: CD103 is expressed in several immune cell types but in the context of the intratumoral immune response may be most important as a marker of antigen-activated CD8 T cells.Methods: We have examined the prognostic significance of CD103 TILs in breast cancer by IHC in a cohort of 424 breast cancer patients.Results: CD103 TILs were present in all subtypes but were more abundant in ER-negative tumors where CD103 TILs were preferentially localized to the intraepithelial compartment. CD103 was associated with tumor size, tumor grade, and ER/PR status (P < 0.05). CD103 TIL density and the epithelial to stromal ratio was highest in the basal-like tumors. Intraepithelial CD103 but not intrastromal CD103 was associated with better relapse-free and overall survival in basal-like subtype tumors [HR ¼ 0.28; 95% confidence interval (CI), 0.17-0.72; P ¼ 0.0047 and HR ¼ 0.25; 95% CI, 0.17-0.66; P ¼ 0.0017, respectively). CD8 status showed similar but less significant associations, but the combination of dual CD103 þ CD8þ TIL status was the most strongly prognostic combination for relapse-free and overall survival (HR ¼ 0.10; 95% CI, 0.07-0.62; P ¼ 0.006 and HR ¼ 0.09; 95% CI, 0.07-0.57; P ¼ 0.003, respectively). Conclusions: CD103 TILs are indicative of a good prognosis specifically within the basal-like subtype of breast cancer. Clin Cancer Res; 22(24); 6290-7. Ó2016 AACR.

Purpose: Tumors with high mutation load are thought to engender stronger immune responses, which in turn promote prolonged patient survival. To investigate this, we assessed tumor-infiltrating lymphocytes (TILs) and immunosuppressive factors across the 4 molecular subtypes of endometrial cancer, which have characteristic mutation rates ranging from low to ultra-high.Experimental Design: A total of 460 endometrial cancers were stratified by ProMisE (Proactive Molecular Risk Classifier in Endometrial cancer) into 4 molecular subtypes: mismatch repair-deficient (MMRd), POLE mutant (POLE), p53 abnormal (p53abn), and p53 wild-type (p53wt). Immune markers (CD3, CD8, CD79a, CD138, PD-1, PD-L1, FoxP3, IDO-1) were quantified by multiplex IHC and tested for associations with ProM-isE subtype, survival, and other clinicopathologic parameters.Results: Two major TIL patterns were observed. TIL high tumors harbored dense T-and B-lineage infiltrates and multiple immunosuppressive features and were common in molecular subtypes associated with high mutation load (MMRd and POLE); however, equally strong responses were seen in significant numbers of p53abn and p53wt tumors, which have characteristically low mutation loads. TIL low tumors were generally devoid of immunologic features and were more prevalent in p53abn and p53wt endometrial cancers, yet were also seen in MMRd and POLE subtypes. In multivariable models involving ProMisE subtype, T-cell markers, and TIL clusters, only ProMisE showed independent prognostic significance.Conclusions: Immune response correlates with endometrial cancer molecular subtype but does not carry independent prognostic significance. Profound variation in immune response is seen across and within endometrial cancer molecular subtypes, suggesting that assessment of immune response rather than molecular subtype may better predict response to immunotherapy.

Engineering T cells with chimeric antigen receptors (CARs) is an effective method for directing T cells to attack tumors, but may cause adverse side effects such as the potentially lethal cytokine release syndrome. Here the authors show that the T cell antigen coupler (TAC), a chimeric receptor that co-opts the endogenous TCR, induces more efficient anti-tumor responses and reduced toxicity when compared with past-generation CARs. TAC-engineered T cells induce robust and antigen-specific cytokine production and cytotoxicity in vitro, and strong anti-tumor activity in a variety of xenograft models including solid and liquid tumors. In a solid tumor model, TAC-T cells outperform CD28-based CAR-T cells with increased anti-tumor efficacy, reduced toxicity, and faster tumor infiltration. Intratumoral TAC-T cells are enriched for Ki-67+ CD8+ T cells, demonstrating local expansion. These results indicate that TAC-T cells may have a superior therapeutic index relative to CAR-T cells.

CD74 (invariant chain) plays a role in MHC class II antigen presentation. We assessed CD74 and MHCII expression in tumor cells, as well as CD8, CD4, and CD68 tumor infiltrating leucocyte (TIL) density by immunohistochemistry in a cohort of 492 breast cancer patients. CD74 expression was associated with poor prognostic markers including patient age, tumor grade, ER status, non-Luminal A subtypes, and with MHCII expression and higher TIL densities, particularly in the Basal-like subgroup. Univariate analysis showed a favorable prognostic effect of CD74 (Hazard ratio = 0.46, 95% CI = 0.26–0.89, p = 0.022) and for combined CD74/MHCII (Hazard ratio = 0.26, 95% CI = 0.17–0.81, p = 0.014) positive status for overall survival that was only manifested in the Basal-like subgroup. CD74 and MHCII expression is associated with patient survival in Basal-like breast cancer, and the association with TIL may reflect an effective intratumoral immune response.