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Tissue localization is a critical determinant of T cell immunity. CD8+ T cells are contact-dependent killers, which requires them to physically be within the tissue of interest to kill peptide–MHC class I-bearing target cells. Following their migration and extravasation into tissues, T cells receive many extrinsic cues from the local microenvironment, and these signals shape T cell differentiation, fate and function. Because major organ systems are variable in their functions and compositions, they apply disparate pressures on T cells to adapt to the local microenvironment. Additional complexity arises in the context of malignant lesions (either primary or metastatic), and this has made understanding the factors that dictate T cell function and longevity in tumours challenging. Moreover, T cell differentiation state influences how cues from the microenvironment are interpreted by tissue-infiltrating T cells, highlighting the importance of T cell state in the context of tissue biology. Here, we review the intertwined nature of T cell differentiation state, location, survival and function, and explain how dysfunctional T cell populations can adopt features of tissue-resident memory T cells to persist in tumours. Finally, we discuss how these factors have shaped responses to cancer immunotherapy.Here, Schenkel and Pauken consider how specific patterns of T cell trafficking and localization in tissue microenvironments shape their immune functions in acute infection and cancer settings. They further consider the relevance of this for the efficacy of immune checkpoint blockade therapy in the clinic.

The immune system of laboratory mice raised in an ultra-hygienic environment resembles that ofnewborn humans, but can be induced to resemble the immune system of adult humans or 'dirty' mice by co-housing with pet store-bought mice. Do 'dirty' mice make better immunological models? The laboratory mouse is by far the dominant model organism for in vivo immunological research which — particularly in the light of disappointing results obtained with some recent transfers of disease treatments from laboratory to clinic — raises the question of how accurately the model reflects the human immune system. These authors compare the immune status of laboratory mice with that of feral mice and with mice bought commercially as pets. They find that the immune system of the ubiquitous laboratory 'specific pathogen free' mouse approximates that of human neonates, rather than human adults. Co-housing laboratory mice with 'pet store' mice leads to maturation of the immune system, making it more similar to that of the human adult, and resulting in increased resistance in several models of infection. The use of such 'dirty' mice could supplement current models to either increase translational potential to human disease or to better inform the efficacy of preclinical prophylactic and therapeutic modalities. Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice—like newborn, but not adult, humans—lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans.

Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated “hot” tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts “cold” tumors to hot, generates systemic CD8⁺ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.

With increasing attention on the essential roles of the tumour microenvironment in recent years, the nervous system has emerged as a novel and crucial facilitator of cancer growth. In this Review, we describe the foundational, translational, and clinical advances illustrating how nerves contribute to tumour proliferation, stress adaptation, immunomodulation, metastasis, electrical hyperactivity and seizures, and neuropathic pain. Collectively, this expanding knowledge base reveals multiple therapeutic avenues for cancer neuroscience that warrant further exploration in clinical studies. We discuss the available clinical data, including ongoing trials investigating novel agents targeting the tumour–nerve axis, and the therapeutic potential for repurposing existing neuroactive drugs as an anti-cancer approach, particularly in combination with established treatment regimens. Lastly, we discuss the clinical challenges of these treatment strategies and highlight unanswered questions and future directions in the burgeoning field of cancer neuroscience.

Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer that remains among the most lethal of solid tumor malignancies. Recent genomic sequencing studies have identified many recurrently mutated genes in human SCLC tumors. However, the functional roles of most of these genes remain to be validated. Here, we have adapted the CRISPR-Cas9 system to a well-established murine model of SCLC to rapidly model loss-of-function mutations in candidate genes identified from SCLC sequencing studies. We show that loss of the gene p107 significantly accelerates tumor progression. Notably, compared with loss of the closely related gene p130, loss of p107 results in fewer but larger tumors as well as earlier metastatic spread. In addition, we observe differences in proliferation and apoptosis as well as altered distribution of initiated tumors in the lung, resulting from loss of p107 or p130. Collectively, these data demonstrate the feasibility of using the CRISPR-Cas9 system to model loss of candidate tumor suppressor genes in SCLC, and we anticipate that this approach will facilitate efforts to investigate mechanisms driving tumor progression in this deadly disease.

Key Points Although the classical model of T cell entry into secondary lymphoid organs suggests that this requires CD62L, CC-chemokine receptor 7 (CCR7) and lymphocyte function-associated antigen 1 (LFA1) to support the rolling, activation and arrest of T cells at high endothelial venules, the rules are different for T cell entry in mucosal-associated lymphoid tissue, splenic white pulp and inflamed lymph nodes. T cells may also enter a lymph node downstream of a neighbouring lymph node via the afferent lymphatics. Intranodal motility is regulated by CCR7, while egress of T cells is dictated by responsiveness to sphingosine-1-phosphate (S1P) gradients. Migration of activated T cells into non-lymphoid tissues may be somewhat promiscuous; however, it is influenced by developmental cues that reflect the site of T cell priming as well as the inflammatory status of the target tissue. Effector T cells use various strategies to increase the efficiency of their scanning for antigen in non-lymphoid tissues. These strategies include the use of Lévy walks and adopting a 'dendritic-like' morphology in order to simultaneously contact multiple targets. After pathogen clearance, memory T cells found in non-lymphoid tissues are either tissue-resident or re-circulating. Resident memory T cells adapt their phenotype in response to local cues within non-lymphoid tissues, and this may optimize site-specific protective immune responses by affecting T cell function and allowing for their long-term maintenance within these unique environments. Non-lymphoid organs comprise many tissue types and compartments, each of which may be populated by different T cell subsets. Histological analyses as well as intravascular labelling of capillary-bound T cells may be necessary to place populations in their proper anatomical context. The central memory T cell and effector memory T cell nomenclature suffers from an absence of universally accepted definitions. Refining these terms will be necessary for the field to optimally conceptualize and communicate the additional complexity of migration and location-dependent T cell differentiation states that have recently been characterized. Here, the authors describe how T cell trafficking to distinct tissues is regulated under inflammatory and non-inflammatory conditions. They explain how the unique migratory properties of different T cell populations are intimately connected to their functions and, furthermore, discuss whether the ever-expanding nomenclature for T cell subsets is a help or a hindrance to immunologists. T cells function locally. Accordingly, T cells' recognition of antigen, their subsequent activation and differentiation, and their role in the processes of infection control, tumour eradication, autoimmunity, allergy and alloreactivity are intrinsically coupled with migration. Recent discoveries revise our understanding of the regulation and patterns of T cell trafficking and reveal limitations in current paradigms. Here, we review classic and emerging concepts, highlight the challenge of integrating new observations with existing T cell classification schemes and summarize the heuristic framework provided by viewing T cell differentiation and function first through the prism of migration.

Tissue-resident effector memory T cells respond rapidly after reencountering antigen. Masopust and colleagues show that memory CD8 + T cells also induce the release of chemokines, then recruit more memory cells to the site of infection. CD8 + T cells eliminate intracellular infections through two contact-dependent effector functions: cytolysis and secretion of antiviral cytokines. Here we identify the following additional function for memory CD8 + T cells that persist at front-line sites of microbial exposure: to serve as local sensors of previously encountered antigens that precipitate innate-like alarm signals and draw circulating memory CD8 + T cells into the tissue. When memory CD8 + T cells residing in the female mouse reproductive tract encountered cognate antigen, they expressed interferon-γ (IFN-γ), potentiated robust local expression of inflammatory chemokines and induced rapid recruitment of circulating memory CD8 + T cells. Anamnestic responses in front-line tissues are thus an integrated collaboration between front-line and circulating populations of memory CD8 + T cells, and vaccines should establish both populations to maximize rapid responses.

The pathogen recognition theory dictates that, upon viral infection, the innate immune system first detects microbial products and then responds by providing instructions to adaptive CD8 T cells. Here, we show in mice that tissue resident memory CD8 T cells (TRM cells), non-recirculating cells located at common sites of infection, can achieve near-sterilizing immunity against viral infections by reversing this flow of information. Upon antigen resensitization within the mouse female reproductive mucosae, CD8⁺ TRM cells secrete cytokines that trigger rapid adaptive and innate immune responses, including local humoral responses, maturation of local dendritic cells, and activation of natural killer cells. This provided near-sterilizing immunity against an antigenically unrelated viral infection. Thus, CD8⁺ TRM cells rapidly trigger an antiviral state by amplifying receptor-derived signals from previously encountered pathogens.

Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 Tcells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory Tcells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector Tcells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (T ex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating T ex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade. The clinical benefit of anti-PD-1 antibody treatment is dependent on the extent to which exhausted CD8 T cells are reinvigorated in relation to the tumour burden of the patient. Blood biomarkers of blockade therapy response Only a small proportion of patients with advanced melanoma currently experience a long-term clinical benefit from therapeutic PD-1 blockade. Until now, blood-based profiling has not been widely explored as a means to understand the mechanisms of PD-1 blockade. In this study, Alexander Huang et al . analyse CD8 T cells in the blood and show that the clinical benefit of PD-1 blockade depends on the extent to which it reinvigorates exhausted CD8 T cells in relation to the pre-treatment tumour burden. Identifying the ratio of tumour burden to CD8 T-cell reinvigoration may help to predict how well a patient will respond to PD-1-blocking therapy.