New clonotypes recruited (by Staff Sergeant K. Brasier via U.S. Air Force)To identify which tumor-specific T cells are active after anti–PD-1 therapy of basal cell carcinomas, single cells from biopsies before and after treatment were analyzed for gene expression and TCR usage. T cells already exhausted before anti–PD-1 therapy were not reactivated. Instead, novel clonotypes (only a small fraction of which had previously expressed TCF7) replaced those, transiting from memory to activated states. This was also true of squamous cell carcinoma, suggesting that checkpoint blockade prompts a new wave of immunoevolution and that the tumor's ability to constantly attract new T cells may be key to successful responses.Yost KE, …, Chang HY. Nat Med 2019 Aug 1;25:1251–9.CD163+ TAMs infiltrating melanomas (from Fig. 1C Etzerodt et al. J Exp Med 2019)Tumor-associated macrophages (TAMs) can contribute to tumor cell immune evasion, which is dependent on their phenotype and the tumor microenvironment (TME). Barkal et al. show that ovarian and breast cancers overexpress CD24, which relays “don't eat me” signals to TAMs via interaction with Siglec-10. Etzerodt et al. demonstrate that in melanomas refractory to anti–PD-1, CD163+ TAMs are elevated. Immunotherapies that target either surface molecules (such as CD24) or cell types (such as CD163+ TAMs) that promote immune evasion can alter the TME, resulting in enhanced antitumor immunity.Barkal AA, …, Weissman IL. Nature 2019 Aug 15;572:392–6.Etzerodt A, …, Lawrence T. J Exp Med 2019 Aug 2. DOI: 10.1084/jem.20182124.Optimizing the anti–PD1 schedule (by Best Picko via Flickr)Optimizing the efficacy of combination therapies involves determining their ideal schedule. In anti–PD-1–resistant murine tumor models, peptide vaccination plus anti–PD-1 slows tumor growth, whereas exposure to anti–PD-1 before combination treatment abrogates effectiveness. Anti–PD-1 causes suboptimal antigen priming of intratumoral CD8+ T cells, leading to increased dysfunction, higher PD-1+ CD38hi frequency, and more death. Anti–PD-1 responder patients have fewer intratumoral PD-1+ CD38+ CD8+ T cells compared to nonresponders, suggesting a predictive biomarker for anti–PD-1. Thus, T-cell priming prior to anti–PD-1 therapy is crucial for its efficacy.Verma V, …, Khleif SN. Nat Immunol 2019 Sep 1;20:1231–43.IFN opposing itself (via Max Pixel)Resistance to immune checkpoint blockade (ICB) is complex. Tumor-produced IFNγ sets up feedback loops that promote intrinsic tumor resistance and inhibit innate and adaptive immunity. Blocking IFN-stimulated gene expression from MHC class Ilow tumors can restore ICB responsiveness, stimulating tumor killing via TRAIL by NK and type 1 innate lymphoid cells (ILC1s). ICB treatment enhances IFNγ produced by CD8+ exhausted T (TEX) cells (that had been inactivated through PD-1 engagement), which supports NK/ILC1 cell maturation; TEX cells can also kill those tumor cells with adequate MHC class I, via the granzyme B/perforin pathway.Benci JL, …, Minn AJ. Cell 2019 Aug 8;178:933–48.e14.Engineering increased functionality (by N. Pawar via MotorsGarage)The affinity of a TCR for its target can affect antileukemia responses in patients with acute myeloid leukemia (AML) treated by hematopoietic cell transplantation (HCT). Engineered T cells bearing a high-affinity TCR targeting antigen WT1 (called TCRC4) can kill AML cells, are polyfunctional, and have increased persistence in vivo. When infused into patients after HCT, TCRC4 T cells reduced AML relapse. Thus, these engineered T cells could extend antileukemia T-cell persistence and reduce relapse in high-risk AML patients after HCT or other standards of care.Chapuis AG, …, Greenberg PD. Nat Med 2019 Jul 3;25:1064–72.Conditioning of hosts (by didkog via Pixabay)The efficacy of adoptive cell therapy (ACT) for cancer depends on prior lymphodepletion of recipients: IL-1β increases after this “conditioning.” Adding IL-1β to ACT therapy greatly improves therapeutic responses by increasing the number of effector CD8+ T cells in tumors and tumor-draining lymph nodes compared to ACT alone, in an IL-2/IL-15–mediated manner. IL-1β improves the trafficking of CD8+ T cells into peripheral organs and primes the host to better support effector CD8+ T-cell survival in these organs. Thus, treating patients with IL-1β may improve ACT efficacy.Lee P-H, …, Restifo NP. J Exp Med 2019 Aug 12. DOI: 10.1084/jem.20181218.
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Apr 1, 2020
Jaroslaw Kierkus + 11
Open Access
