The success of checkpoint inhibitors has accelerated the clinical implementation of a vast mosaic of single agents and combination immunotherapies. However, the lack of clinical translation for a ...number of immunotherapies as monotherapies or in combination with checkpoint inhibitors has clarified that new strategies must be employed to advance the field. The next chapter of immunotherapy should examine the immuno-oncology therapeutic failures, and consider the complexity of immune cell-cancer cell interactions to better design more effective anticancer drugs. Herein, we briefly review the history of immunotherapy and checkpoint blockade, highlighting important clinical failures. We discuss the critical aspects - beyond T cell co-receptors - of immune processes within the tumour microenvironment (TME) that may serve as avenues along which new therapeutic strategies in immuno-oncology can be forged. Emerging insights into tumour biology suggest that successful future therapeutics will focus on two key factors: rescuing T cell homing and dysfunction in the TME, and reappropriating mononuclear phagocyte function for TME inflammatory remodelling. New drugs will need to consider the complex cell networks that exist within tumours and among cancer types.
Although widely studied as a neurotransmitter, T cell-derived acetylcholine (ACh) has recently been reported to play an important role in regulating immunity. However, the role of lymphocyte-derived ...ACh in viral infection is unknown. Here, we show that the enzyme choline acetyltransferase (ChAT), which catalyzes the rate-limiting step of ACh production, is robustly induced in both CD4
and CD8
T cells during lymphocytic choriomeningitis virus (LCMV) infection in an IL-21-dependent manner. Deletion of
within the T cell compartment in mice ablated vasodilation in response to infection, impaired the migration of antiviral T cells into infected tissues, and ultimately compromised the control of chronic LCMV clone 13 infection. Our results reveal a genetic proof of function for ChAT in T cells during viral infection and identify a pathway of T cell migration that sustains antiviral immunity.
Cancer cells have higher reactive oxygen species (ROS) than normal cells, due to genetic and metabolic alterations. An emerging scenario is that cancer cells increase ROS to activate protumorigenic ...signaling while activating antioxidant pathways to maintain redox homeostasis. Here we show that, in basal-like and BRCA1-related breast cancer (BC), ROS levels correlate with the expression and activity of the transcription factor aryl hydrocarbon receptor (AhR). Mechanistically, ROS triggers AhR nuclear accumulation and activation to promote the transcription of both antioxidant enzymes and the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). In a mouse model of BRCA1-related BC, cancer-associated AhR and AREG control tumor growth and production of chemokines to attract monocytes and activate proangiogenic function of macrophages in the tumor microenvironment. Interestingly, the expression of these chemokines as well as infiltration of monocyte-lineage cells (monocyte and macrophages) positively correlated with ROS levels in basal-like BC. These data support the existence of a coordinated link between cancer-intrinsic ROS regulation and the features of tumor microenvironment. Therapeutically, chemical inhibition of AhR activity sensitizes human BC models to Erlotinib, a selective EGFR tyrosine kinase inhibitor, suggesting a promising combinatorial anticancer effect of AhR and EGFR pathway inhibition. Thus, AhR represents an attractive target to inhibit redox homeostasis and modulate the tumor promoting microenvironment of basal-like and BRCA1-associated BC.
Myeloid cells contribute to tumor progression, but how the constellation of receptors they express regulates their functions within the tumor microenvironment (TME) is unclear. We demonstrate that ...Fcmr (Toso), the putative receptor for soluble IgM, modulates myeloid cell responses to cancer. In a syngeneic melanoma model, Fcmr ablation in myeloid cells suppressed tumor growth and extended mouse survival. Fcmr deficiency increased myeloid cell population density in this malignancy and enhanced anti-tumor immunity. Single-cell RNA sequencing of Fcmr-deficient tumor-associated mononuclear phagocytes revealed a unique subset with enhanced antigen processing/presenting properties. Conversely, Fcmr activity negatively regulated the activation and migratory capacity of myeloid cells in vivo, and T cell activation by bone marrow-derived dendritic cells in vitro. Therapeutic targeting of Fcmr during oncogenesis decreased tumor growth when used as a single agent or in combination with anti-PD-1. Thus, Fcmr regulates myeloid cell activation within the TME and may be a potential therapeutic target.
In short-lived animals, innate immunity is an important component of fitness and quality. Although receivers cannot generally assess a signaler’s immune function directly, sexually selected displays ...such as birdsong may reflect past or current condition. We investigated the degree to which song complexity and consistency, thought to reflect condition over different developmental timescales, predict multiple aspects of innate immunity in male song sparrows (Melospiza melodia). We also investigated correlations among immune measures. Noncellular components of innate immunity (soluble blood proteins including natural antibody and other protective proteins) were negatively related to cellular (phagocytosis-based) components, suggesting trade-offs within innate immune protection. This pattern underscores the risk of inferring “immunocompetence” from a single metric. Song complexity, a permanent trait in this species, was positively related to noncellular relative to cellular immune components and may thus provide information as to the singer’s innate immune strategy (investment in noncellular vs. cellular activity). Such a relationship could arise through shared timing of song learning and antibody repertoire development in early life. Singing consistency, thought to track variation in current condition and measured at both whole-song and syllable scales, did not predict any immune measures. Developmental timing of signals thus appears to influence their information content.
Developmental Stress, Condition, and Birdsong Schmidt, Kim L.; MacDougall-Shackleton, Elizabeth A.; Kubli, Shawn P. ...
Integrative and comparative biology,
10/2014, Letnik:
54, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Sexual-selection theory posits that ornaments and displays can reflect a signaler’s condition, which in turn is affected both by recent and developmental conditions. Moreover, developmental ...conditions can induce correlations between sexually selected and other traits if both types of traits exhibit developmental phenotypic plasticity in response to stressors. Thus, sexually selected traits may reflect recent and/or developmental characteristics of signalers. Here, we review data on the relationships between birdsong, a sexually selected trait, and developmental and current condition of birds from a long-term study of a population of song sparrows (Melospiza melodia). Field studies of free-living birds indicate that the complexity of a male’s songs, a permanent trait, reflects the size of a song-control region of his brain (HVC), and is correlated with body size and several parameters of immunity, specifically investment in protective proteins. However, the performance of a male’s songs, a dynamic trait, is not correlated to immune investment. Complexity of song is correlated with the glucocorticoid stress-response, and in some years response to stress predicts overwinter survival. Experimental manipulations have revealed that stressors in early life impair development of HVC, but that HVC recovers in size by adulthood. These manipulations result in impaired song-complexity and song-learning, but not song-performance. Experimental developmental stressors also affect growth, endocrine physiology, metabolism, and immune-function, often in a sex-specific manner. Combined, these studies suggest that song-complexity provides reliable information about early developmental experience, and about other traits that have critical developmental periods. Birdsong thus provides a multi-faceted sexually selected trait that may be an indicator both of developmental and recent conditions.
Multiple components of the immune system are modulated by environmental factors, including exposure to stressors. In particular, chronic stressors can impair development of the immune system, leading ...to alterations in immune function in adulthood. While these effects have been well established in mammals, less is known about how developmental stress modulates immunity in nonmammalian species. We determined the long-term effects of exposure to early-life stressors on immunity in song sparrows including the swelling response to phytohemagglutinin (PHA) and several measures of constitutive innate immunity. Song sparrows were reared in captivity from 3 d of age and exposed to control conditions, food restriction, or corticosterone (CORT) treatment. Males exposed to food restriction or CORT treatment had less swelling of the wing web in response to PHA than control males; however, neither treatment affected the swelling response to PHA in females. The treatments also had sex-specific effects on constitutive innate immune function. Specifically, CORT-treated males had lower antimicrobial capacity toward a strain of the bacteriumE. colibut higher antimicrobial activity toward a strain of the fungusCandida albicanscompared to food-restricted or control males. In contrast, neither treatment affected constitutive innate immunity in females. These results suggest that male and female song sparrows may differ in how they allocate resources to development of the immune system when reared in stressful or food-limited conditions.
Tumors are heterogeneously comprised of various cell types that make up a complex tissue-like structure, where cancer cells interact with various non-malignant cells. Immune cells represent one of ...these non-malignant cell types, and are particularly suitable as targets for anti-cancer therapeutics. Therapeutics that target the immune system (Immunotherapeutics), which are currently in clinical application, aim to restore immune responses to cancer cells by inhibiting the immune checkpoints that dampen lymphocyte responses. The efficacy of these immunotherapeutics results in good prognosis for some patients. Unfortunately, there are many non-responders, and we are only now just starting to discern the mechanisms that govern response efficacy. Targeting these immune checkpoints, with αPD-1 and αCTLA-4 monoclonal antibodies, restores anti-tumor effector function to dysfunctional tumor infiltrating lymphocytes, and facilitates the reduction of regulatory T cells. However, there are other aspects of tumor immunology that are unaffected by these drugs. Combinatorial treatment strategies that amplify the effects of current immune modulating drugs are thus predicted to enhance response efficacy.It is well established that myeloid cells contribute to oncogenesis, but how the constellation of receptors they express regulates their functions within the tumor microenvironment is less clear. Furthermore, cells of the mononuclear phagocytic system have the potential to function in a pro-tumoral capacity, or to promote anti-tumor immunity for cancer cell elimination. Here we demonstrate that autocrine and paracrine EGFR signaling between intratumoral macrophages and cancer cells facilitates tumorigenesis through macrophage mediated trophic support. Specifically, we show a novel AhR-AREG axis facilitates maintenance of the tumor microenvironment in BRCA1-associated breast cancer. Alternatively, in a syngeneic melanoma model we illustrate that Toso (FCMR), the putative receptor for soluble IgM, modulates myeloid cell responses to cancer to inhibit anti-tumor immunity. Furthermore, Toso negatively regulated the activation and migratory capacity of skin-associated myeloid cells in vivo, and bone-marrow derived dendritic cell-dependent T cell activation in vitro. Importantly, preliminary data indicates therapeutically targeting Ahr in BRCA1-associated cancers, or Toso in melanoma, may improve patient prognosis. Overall, these results suggest that targeting myeloid cell function within the TME represents a potential therapeutic avenue for bolstering current checkpoint immunotherapeutics.
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