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Cancer Research     Hybrid Journal   (Followers: 63, SJR: 4.26, CiteScore: 7)
Clinical Cancer Research     Hybrid Journal   (Followers: 46, SJR: 4.929, CiteScore: 8)
Cancer Discovery     Hybrid Journal   (Followers: 25, SJR: 6.996, CiteScore: 5)
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Cancer Immunology Research
Number of Followers: 16  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 2326-6066 - ISSN (Online) 2326-6074
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  • A Sampling of Highlights from the Literature: Article Recommendations from
           Our Deputy and Senior Editors

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      Pages: 145 - 145
      PubDate: 2022-02-03T04:40:25-08:00
      DOI: 10.1158/2326-6066.CIR-10-2-WWR
      Issue No: Vol. 10, No. 2 (2022)
       
  • Reversing T-cell Exhaustion in Cancer: Lessons Learned from PD-1/PD-L1
           Immune Checkpoint Blockade

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      Authors: Budimir, N; Thomas, G. D, Dolina, J. S, Salek-Ardakani, S.
      Pages: 146 - 153
      Abstract: Anti–PD-1/PD-L1 immune checkpoint blockade (ICB) therapy has revolutionized the treatment of many types of cancer over the past decade. The initial therapeutic hypothesis underlying the mechanism of anti–PD-1/PD-L1 ICB was built around the premise that it acts locally in the tumor, reversing the exhaustion of PD-1hiCD8+ T cells by "releasing the brakes." However, recent studies have provided unprecedented insight into the complexity within the CD8+ T-cell pool in the tumor microenvironment (TME). Single-cell RNA sequencing and epigenetic profiling studies have identified novel cell surface markers, revealing heterogeneity within CD8+ T-cell states classified as unique. Moreover, these studies highlighted that following ICB, CD8+ T-cell states within and outside the TME possess a differential capacity to respond, mobilize to the TME, and seed an effective antitumor immune response. In aggregate, these recent developments have led to a reevaluation of our understanding of both the underlying mechanisms and the sites of action of ICB therapy. Here, we discuss the evidence for the reversibility of CD8+ T-cell exhaustion after ICB treatment and its implication for the further development of cancer immunotherapy.
      PubDate: 2022-02-03T04:40:25-08:00
      DOI: 10.1158/2326-6066.CIR-21-0515
      Issue No: Vol. 10, No. 2 (2022)
       
  • NKG7 Is Required for Optimal Antitumor T-cell Immunity

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      Authors: Li, X.-Y; Corvino, D, Nowlan, B, Aguilera, A. R, Ng, S. S, Braun, M, Cillo, A. R, Bald, T, Smyth, M. J, Engwerda, C. R.
      Pages: 154 - 161
      Abstract: Tumor antigen-specific CD8+ T cells play a critical role in antitumor immunity. Clinical trials reinvigorating the immune system via immune checkpoint blockade (ICB) have shown remarkable clinical promise. Numerous studies have identified an association between NKG7 expression and patient outcome across different malignancies. However, aside from these correlative observations, very little is known about NKG7 and its role in antitumor immunity. Herein, we utilized single-cell RNA sequencing (scRNA-seq) datasets, NKG7-deficient mice, NKG7-reporter mice, and mouse tumor models to investigate the role of NKG7 in neoantigen-mediated tumor rejection and ICB immunotherapy. scRNA-seq of tumors from patients with metastatic melanoma or head and neck squamous cell carcinoma revealed that NKG7 expression is highly associated with cytotoxicity and specifically expressed by CD8+ T cells and natural killer (NK) cells. Furthermore, we identified a key role for NKG7 in controlling intratumor T-cell accumulation and activation. NKG7 was upregulated on intratumor antigen-specific CD8+ T cells and NK cells and required for the accumulation of T cells in the tumor microenvironment. Accordingly, neoantigen-expressing mouse tumors grew faster in Nkg7-deficient mice. Strikingly, efficacy of single or combination ICB was significantly reduced in Nkg7-deficient mice.See related article by Wen et al., p. 162.
      PubDate: 2022-02-03T04:40:25-08:00
      DOI: 10.1158/2326-6066.CIR-20-0649
      Issue No: Vol. 10, No. 2 (2022)
       
  • NKG7 Is a T-cell-Intrinsic Therapeutic Target for Improving Antitumor
           Cytotoxicity and Cancer Immunotherapy

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      Authors: Wen, T; Barham, W, Li, Y, Zhang, H, Gicobi, J. K, Hirdler, J. B, Liu, X, Ham, H, Peterson Martinez, K. E, Lucien, F, Lavoie, R. R, Li, H, Correia, C, Monie, D. D, An, Z, Harrington, S. M, Wu, X, Guo, R, Dronca, R. S, Mansfield, A. S, Yan, Y, Markovic, S. N, Park, S. S, Sun, J, Qin, H, Liu, M. C, Vasmatzis, G, Billadeau, D. D, Dong, H.
      Pages: 162 - 181
      Abstract: Cytotoxic CD8+ T cells (CTL) are a crucial component of the immune system notable for their ability to eliminate rapidly proliferating malignant cells. However, the T-cell intrinsic factors required for human CTLs to accomplish highly efficient antitumor cytotoxicity are not well defined. By evaluating human CD8+ T cells from responders versus nonresponders to treatment with immune checkpoint inhibitors, we sought to identify key factors associated with effective CTL function. Single-cell RNA-sequencing analysis of peripheral CD8+ T cells from patients treated with anti–PD-1 therapy showed that cells from nonresponders exhibited decreased expression of the cytolytic granule-associated molecule natural killer cell granule protein-7 (NKG7). Functional assays revealed that reduced NKG7 expression altered cytolytic granule number, trafficking, and calcium release, resulting in decreased CD8+ T-cell–mediated killing of tumor cells. Transfection of T cells with NKG7 mRNA was sufficient to improve the tumor-cell killing ability of human T cells isolated from nonresponders and increase their response to anti–PD-1 or anti–PD-L1 therapy in vitro. NKG7 mRNA therapy also improved the antitumor activity of murine tumor antigen–specific CD8+ T cells in an in vivo model of adoptive cell therapy. Finally, we showed that the transcription factor ETS1 played a role in regulating NKG7 expression. Together, our results identify NKG7 as a necessary component for the cytotoxic function of CD8+ T cells and establish NKG7 as a T-cell–intrinsic therapeutic target for enhancing cancer immunotherapy.See related article by Li et al., p. 154.
      PubDate: 2022-02-03T04:40:25-08:00
      DOI: 10.1158/2326-6066.CIR-21-0539
      Issue No: Vol. 10, No. 2 (2022)
       
  • Remodeling Chondroitin-6-Sulfate-Mediated Immune Exclusion Enhances
           Anti-PD-1 Response in Colorectal Cancer with Microsatellite Stability

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      Authors: Wu, Q; Huang, Q, Jiang, Y, Sun, F, Liang, B, Wang, J, Hu, X, Sun, M, Ma, Z, Shi, Y, Liang, Y, Tan, Y, Zeng, D, Yao, F, Xu, X, Yao, Z, Li, S, Rong, X, Huang, N, Sun, L, Liao, W, Shi, M.
      Pages: 182 - 199
      Abstract: Metastatic microsatellite-stable (MSS) colorectal cancer rarely responds to immune checkpoint inhibitors (ICI). Metabolism heterogeneity in the tumor microenvironment (TME) presents obstacles to antitumor immune response. Combining transcriptome (The Cancer Genome Atlas MSS colorectal cancer, n = 383) and digital pathology (n = 96) analysis, we demonstrated a stroma metabolism–immune excluded subtype with poor prognosis in MSS colorectal cancer, which could be attributed to interaction between chondroitin-6-sulfate (C-6-S) metabolites and M2 macrophages, forming the "exclusion barrier" in the invasive margin. Furthermore, C-6-S derived from cancer-associated fibroblasts promoted co–nuclear translocation of pSTAT3 and GLI1, activating the JAK/STAT3 and Hedgehog pathways. In vivo experiments with C-6-S–targeted strategies decreased M2 macrophages and reprogrammed the immunosuppressive TME, leading to enhanced response to anti–PD-1 in MSS colorectal cancer. Therefore, C-6-S–induced immune exclusion represents an "immunometabolic checkpoint" that can be exploited for the application of combination strategies in MSS colorectal cancer ICI treatment.
      PubDate: 2022-02-03T04:40:25-08:00
      DOI: 10.1158/2326-6066.CIR-21-0124
      Issue No: Vol. 10, No. 2 (2022)
       
  • Immunomodulation of T- and NK-cell Responses by a Bispecific Antibody
           Targeting CD28 Homolog and PD-L1

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      Authors: Ramaswamy, M; Kim, T, Jones, D. C, Ghadially, H, Mahmoud, T. I, Garcia, A, Browne, G, Zenonos, Z, Puplampu-Dove, Y, Riggs, J. M, Bhat, G. K, Herbst, R, Schofield, D. J, Carlesso, G.
      Pages: 200 - 214
      Abstract: Checkpoint blockade therapies targeting PD-1/PD-L1 and CTLA-4 are clinically successful but also evoke adverse events due to systemic T-cell activation. We engineered a bispecific, mAb targeting CD28 homolog (CD28H), a newly identified B7 family receptor that is constitutively expressed on T and natural killer (NK) cells, with a PD-L1 antibody to potentiate tumor-specific immune responses. The bispecific antibody led to T-cell costimulation, induced NK-cell cytotoxicity of PD-L1–expressing tumor cells, and activated tissue-resident memory CD8+ T cells. Mechanistically, the CD28H agonistic arm of the bispecific antibody reduced PD-L1/PD-1–induced SHP2 phosphorylation while simultaneously augmenting T-cell receptor signaling by activating the MAPK and AKT pathways. This bispecific approach could be used to target multiple immune cells, including CD8+ T cells, tissue-resident memory T cells, and NK cells, in a tumor-specific manner that may lead to induction of durable, therapeutic antitumor responses.
      PubDate: 2022-02-03T04:40:25-08:00
      DOI: 10.1158/2326-6066.CIR-21-0218
      Issue No: Vol. 10, No. 2 (2022)
       
  • Spatial Organization and Prognostic Significance of NK and NKT-like Cells
           via Multimarker Analysis of the Colorectal Cancer Microenvironment

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      Authors: Väyrynen, J. P; Haruki, K, Lau, M. C, Väyrynen, S. A, Ugai, T, Akimoto, N, Zhong, R, Zhao, M, Dias Costa, A, Borowsky, J, Bell, P, Takashima, Y, Fujiyoshi, K, Arima, K, Kishikawa, J, Shi, S.-s, Twombly, T. S, Song, M, Wu, K, Chan, A. T, Zhang, X, Fuchs, C. S, Meyerhardt, J. A, Giannakis, M, Ogino, S, Nowak, J. A.
      Pages: 215 - 227
      Abstract: Although tumor-infiltrating T cells hold a beneficial prognostic role in colorectal cancer, other lymphocytic populations are less characterized. We developed a multiplexed immunofluorescence assay coupled with digital image analysis and machine learning to identify natural killer (NK) cells (NCAM1+CD3–), natural killer T-like (NKT-like) cells (NCAM1+CD3+), and T cells (NCAM1–CD3+) within the PTPRC+ (CD45+) cell population and to measure their granzyme B (GZMB; cytotoxicity marker) and FCGR3A (CD16a; NK-cell maturity marker) expression. We evaluated immune cell densities and spatial configuration in 907 incident colorectal carcinoma cases within two prospective cohort studies. We found that T cells were approximately 100 times more abundant than NK and NKT-like cells. Overall, NK cells showed high GZMB expression and were located closer to tumor cells than T and NKT-like cells. In T and NKT-like cells, GZMB expression was enriched in cells in closer proximity to tumor cells. Higher densities of both T and NKT-like cells associated with longer cancer-specific survival, independent of potential confounders (Ptrend < 0.0007). Higher stromal GZMB+ and FCGR3A+ NK-cell densities associated with longer cancer-specific survival (Ptrend < 0.003). For T and NKT-like cells, greater proximity to tumor cells associated with longer cancer-specific survival (Ptrend < 0.0001). These findings indicate that cytotoxic NCAM1+CD3–GZMB+ NK cells and NCAM1+CD3+ NKT-like cells are relatively rare lymphocytic populations within the colorectal cancer microenvironment and show distinct spatial configuration and associations with patient outcome. The results highlight the utility of a quantitative multimarker assay for in situ, single-cell immune biomarker evaluation and underscore the importance of spatial context for tumor microenvironment characterization.
      PubDate: 2022-02-03T04:40:25-08:00
      DOI: 10.1158/2326-6066.CIR-21-0772
      Issue No: Vol. 10, No. 2 (2022)
       
  • PRDX-1 Supports the Survival and Antitumor Activity of Primary and
           CAR-Modified NK Cells under Oxidative Stress

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      Authors: Klopotowska, M; Bajor, M, Graczyk-Jarzynka, A, Kraft, A, Pilch, Z, Zhylko, A, Firczuk, M, Baranowska, I, Lazniewski, M, Plewczynski, D, Goral, A, Soroczynska, K, Domagala, J, Marhelava, K, Slusarczyk, A, Retecki, K, Ramji, K, Krawczyk, M, Temples, M. N, Sharma, B, Lachota, M, Netskar, H, Malmberg, K.-J, Zagozdzon, R, Winiarska, M.
      Pages: 228 - 244
      Abstract: Oxidative stress, caused by the imbalance between reactive species generation and the dysfunctional capacity of antioxidant defenses, is one of the characteristic features of cancer. Here, we quantified hydrogen peroxide in the tumor microenvironment (TME) and demonstrated that hydrogen peroxide concentrations are elevated in tumor interstitial fluid isolated from murine breast cancers in vivo, when compared with blood or normal subcutaneous fluid. Therefore, we investigated the effects of increased hydrogen peroxide concentration on immune cell functions. NK cells were more susceptible to hydrogen peroxide than T cells or B cells, and by comparing T, B, and NK cells' sensitivities to redox stress and their antioxidant capacities, we identified peroxiredoxin-1 (PRDX1) as a lacking element of NK cells' antioxidative defense. We observed that priming with IL15 protected NK cells' functions in the presence of high hydrogen peroxide and simultaneously upregulated PRDX1 expression. However, the effect of IL15 on PRDX1 expression was transient and strictly dependent on the presence of the cytokine. Therefore, we genetically modified NK cells to stably overexpress PRDX1, which led to increased survival and NK cell activity in redox stress conditions. Finally, we generated PD-L1–CAR NK cells overexpressing PRDX1 that displayed potent antitumor activity against breast cancer cells under oxidative stress. These results demonstrate that hydrogen peroxide, at concentrations detected in the TME, suppresses NK cell function and that genetic modification strategies can improve CAR NK cells' resistance and potency against solid tumors.
      PubDate: 2022-02-03T04:40:25-08:00
      DOI: 10.1158/2326-6066.CIR-20-1023
      Issue No: Vol. 10, No. 2 (2022)
       
  • C3aR Signaling Inhibits NK-cell Infiltration into the Tumor
           Microenvironment in Mouse Models

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      Authors: Nandagopal, S; Li, C. G, Xu, Y, Sodji, Q. H, Graves, E. E, Giaccia, A. J.
      Pages: 245 - 258
      Abstract: Many solid tumors have low levels of cytotoxic CD56dim natural killer (NK) cells, suggesting that CD56dim NK-cell exclusion from the tumor microenvironment (TME) contributes to the decreased response rate of immunotherapy. Complement component 3a (C3a) is known for its tumor-promoting and immunosuppressive roles in solid tumors. Previous reports have implicated the involvement of the C3a receptor (C3aR) in immune cell trafficking into the TME. C3aR is predominantly expressed on the surface of activated cytotoxic NK cells, but a specific role for C3aR in NK-cell biology has not been investigated. Because solid tumors generate elevated C3a and have decreased NK-cell infiltration, we hypothesized that C3aR might play a role in cytotoxic NK-cell recruitment into the TME. Our results indicate that blocking C3aR signaling in NK cells increased NK-cell infiltration into the TME in mouse models and led to tumor regression. Because the critical lymphocyte trafficking integrin LFA-1 orchestrates the migration of activated NK cells, we wanted to gain insight into the interaction between C3aR signaling and LFA-1. Our results demonstrated that direct interaction between C3aR and LFA-1, which led to a high-affinity LFA-1 conformation, decreased NK-cell infiltration into the TME. We propose that approaches to enhance cytotoxic NK-cell infiltration into the TME, through either disrupting C3a and C3aR interaction or inhibiting the formation of high-affinity LFA-1, represent a new strategy to improve the efficiency of immunotherapy for cancer treatment.
      PubDate: 2022-02-03T04:40:25-08:00
      DOI: 10.1158/2326-6066.CIR-21-0435
      Issue No: Vol. 10, No. 2 (2022)
       
  • Expansion of Candidate HPV-Specific T Cells in the Tumor Microenvironment
           during Chemoradiotherapy Is Prognostic in HPV16+ Cancers

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      Authors: Colbert, L. E; El, M. B, Lynn, E. J, Bronk, J, Karpinets, T. V, Wu, X, Chapman, B. V, Sims, T. T, Lin, D, Kouzy, R, Sammouri, J, Biegert, G, Delgado Medrano, A. Y, Olvera, A, Sastry, K. J, Eifel, P. J, Jhingran, A, Lin, L, Ramondetta, L. M, Futreal, A. P, Jazaeri, A. A, Schmeler, K. M, Yue, J, Mitra, A, Yoshida-Court, K, Wargo, J. A, Solley, T. N, Hegde, V, Nookala, S. S, Yanamandra, A. V, Dorta-Estremera, S, Mathew, G, Kavukuntla, R, Papso, C, Ahmed-Kaddar, M, Kim, M, Zhang, J, Reuben, A, Holliday, E. B, Minsky, B. D, Koong, A. C, Koay, E. J, Das, P, Taniguchi, C. M, Klopp, A.
      Pages: 259 - 271
      Abstract: Human papillomavirus (HPV) infection causes 600,000 new cancers worldwide each year. HPV-related cancers express the oncogenic proteins E6 and E7, which could serve as tumor-specific antigens. It is not known whether immunity to E6 and E7 evolves during chemoradiotherapy or affects survival. Using T cells from 2 HPV16+ patients, we conducted functional T-cell assays to identify candidate HPV-specific T cells and common T-cell receptor motifs, which we then analyzed across 86 patients with HPV-related cancers. The HPV-specific clones and E7-related T-cell receptor motifs expanded in the tumor microenvironment over the course of treatment, whereas non–HPV-specific T cells did not. In HPV16+ patients, improved recurrence-free survival was associated with HPV-responsive T-cell expansion during chemoradiotherapy.
      PubDate: 2022-02-03T04:40:25-08:00
      DOI: 10.1158/2326-6066.CIR-21-0119
      Issue No: Vol. 10, No. 2 (2022)
       
 
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