The tumour microenvironment is of critical importance in cancer development and progression and includes the surrounding stromal and immune cells, extracellular matrix, and the milieu of metabolites and signalling molecules in the intercellular space. To support sustained mitotic activity cancer cells must reconfigure their metabolic phenotype. Lactate is the major by-product of such metabolic alterations and consequently, accumulates in the tumour. Lactate actively contributes to immune evasion, a hallmark of cancer, by directly inhibiting immune cell cytotoxicity and proliferation. Furthermore, lactate can recruit and induce immunosuppressive cell types, such as regulatory T cells, tumour-associated macrophages, and myeloid-derived suppressor cells which further suppress anti-tumour immune responses. Given its roles in oncogenesis, measuring intratumoural and systemic lactate levels has shown promise as a both predictive and prognostic biomarker in several cancer types. The efficacies of many anti-cancer therapies are limited by an immunosuppressive TME in which lactate is a major contributor, therefore, targeting lactate metabolism is a priority. Developing inhibitors of key proteins in lactate metabolism such as GLUT1, hexokinase, LDH, MCT and HIF have shown promise in preclinical studies, however there is a corresponding lack of success in human trials so far. This may be explained by a weakness of preclinical models that fail to reproduce the complexities of metabolic interactions in natura. The future of these therapies may be as an adjunct to more conventional treatments.

Gastroesophageal cancers (GOCs) represent some of the most common cancers globally and are linked with poor survival rates. The current standard of care includes multimodal chemotherapy, radiotherapy and surgery. However, up to two-thirds of patients fail to derive benefit from these treatments, underscoring the urgent need to develop better, rationally-designed treatment strategies to enhance survival rates. Certain immunogenic chemotherapies can stimulate anti-tumour immune responses in GOC patients; therefore, combining immune checkpoint inhibitors (ICIs) with chemotherapy to prevent immune exhaustion is an attractive putative therapeutic strategy. Emerging studies demonstrate that immune checkpoint-intrinsic signalling in cancer cells supports several cancer hallmarks in addition to immune evasion, including proliferation, metastasis, glycolysis, DNA repair and chemoresistance. Combining ICIs with chemotherapy may therefore potentially enhance chemosensitivity and suppress a range of immune-dependent and -independent tumourigenic processes in GOCs. This review summarises the current clinical trials investigating the efficacy of ICIs in GOCs. The immunogenic effects of chemotherapies and their effects on immune checkpoint expression is discussed, as is the important and emerging study of novel immune-independent functions of immune checkpoints in cancer.

Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis and incidence is increasing rapidly in the Western world. Multi-modal treatment has improved survival outcomes but only for a minority of patients. Currently no markers have been identified to predict treatment response. This study investigated the association between clinical outcomes and pre-treatment levels of 54 serum proteins in n = 80 patients with EAC. Low tumor regression grade (TRG), corresponding to a favorable treatment response, was linked to prolonged overall survival (OS). CCL4 was higher in patients with a favorable treatment response, while Tie2 and CRP were higher in poor responders. Elevated CCL22 and CCL26 was associated with improved OS, while elevated IL-10 showed a negative association. CCL3, CCL4, IL-1α and IL-12/IL23p40 were highest in individuals with no adverse features of tumor biology, whereas levels of Tie2 and VEGF were lowest in this cohort. CCL4 was also elevated in patients with high tumor lymphocyte infiltration. Comparison of matched pre- and post-treatment serum (n = 28) showed a large reduction in VEGFC, and a concomitant increase in other cytokines, including CCL4. These data link several serum markers with clinical outcomes, highlighting an important role for immune cell trafficking in the EAC antitumor immune response.

Use of immune checkpoint inhibitors (ICIs) with chemotherapy to enhance responses in oesophageal adenocarcinoma (OAC) is an attractive approach. We identified subpopulations of OAC cells expressing inhibitory immune checkpoint (IC) ligands (PD-L1, PD-L2 and CD160) and receptors (PD-1, TIGIT, TIM-3, LAG-3 and A2aR) in vitro and in ex vivo biopsies. Combination chemotherapy regimens FLOT and CROSS promote a more immune-resistant phenotype through upregulation of IC ligands and receptors on OAC cells in vitro. Importantly, this study investigated if OAC cells, enriched for ICs exhibited a more stem-like and senescent-like phentoype. FLOT preferentially upregulates PD-L1 on a stem-like OAC cell phenotype, defined by ALDH activity. Expression of senescence-associated β-galactosidase is induced in a subpopulation of OAC cells following FLOT and CROSS chemotherapy treatment, along with enhanced expression of TIM-3 and A2aR ICs. Blockade of PD-1 signalling in OAC cells induced apoptosis and enhanced FLOT and CROSS chemotherapy toxicity in vitro. Upregulation of ICs on OAC cells following chemotherapy may represent potential mechanisms of chemo-immune resistance. Combination ICIs may be required to enhance the efficacy of chemotherapy and immunotherapy in OAC patients.

Radiotherapy remains one of the contemporary cornerstones of cancer treatment in the neoadjuvant, curative, adjuvant and palliative settings, either in isolation or as a multimodal approach. Moreover, recent advances in targeted immune checkpoint therapy have firmly established immunotherapy as the fourth pillar in cancer therapy alongside surgery, chemotherapy and notably radiotherapy. There is emerging evidence to suggest both radioresistance and reduced efficacy of immune checkpoint blockade (ICB) are potentiated by the tumour microenvironment (TME) and in fact modulating aspects of this immunosuppressive milieu is instrumental to unlocking anti-tumour immunity. The response rates of Upper Gastrointestinal (UGI) malignancies to ICB remains modest at 10–15%, compared to melanoma at 20–40%. Harnessing the effects of radiotherapy through remodelling of the TME using ICB as a radiosensitisor is an avenue showing promise. Here we explore the rationale behind combining radiotherapy with ICB, as a symbiotic relationship in shifting the balance in favour of anti-tumour immunity. We discuss the effects of radiotherapy on immunogenic cell death, the concept of the abscopal effect, the importance of the cGAS STING pathway, and their relevance in the context of the tumour microenvironment. Furthermore, dosing and timing of radiotherapy and ICB is now being evaluated for its synergistic effects on host tumour immunity, and we review the ongoing efforts and current available literature for single agent and dual agent ICB in combination multimodal therapy for both locally advanced operable and metastatic disease of the upper gastrointestinal tract.

Esophagogastric adenocarcinomas (EAC) are obesity-associated malignancies underpinned by severe immune dysregulation and inflammation. Our previous work indicates that NK cells migrate to EAC omentum, where they undergo phenotypic and functional alterations and apoptosis. In this study, we investigate whether such erroneous chemotaxis to omentum is paralleled by compromised NK cell infiltration of EAC patient tumor and examine the role of the inflammatory chemokine fractalkine in shaping the NK cell–mediated response. Our data show diminished NK cell frequencies in EAC tumor compared with those in the circulation and reveal that intratumoral NK cell frequencies decline as visceral obesity increases in EAC patients. Our in vitro findings demonstrate that antagonism of fractalkine receptor CX3CR1 significantly reduces NK cell migration to EAC patient–derived, omental adipose tissue–conditioned media, but not toward tumor-conditioned media. These data suggest fractalkine is a key driver of NK cell chemotaxis to omentum but has a lesser role in NK cell homing to tumor in EAC. We propose that this may offer a novel therapeutic strategy to limit NK cell depletion in the omentum of obese EAC patients, and our data suggest the optimal timing for CX3CR1 antagonism is after neoadjuvant chemoradiotherapy. Our functional studies demonstrate that fractalkine induces the conversion from CX3CR1⁺CD27⁻ to CX3CR1⁻CD27⁺ NK cells and increases their IFN-γ and TNF-α production, indicative of its role in shaping the dominant NK cell phenotype in EAC omentum. This study uncovers crucial and potentially druggable pathways underpinning NK cell dysfunction in obesity-associated cancer and provides compelling insights into fractalkine9s diverse biological functions. Key Points Intratumoral NK cell frequencies decline as visceral obesity increases in EAC. CX3CR1 antagonism has potential to spare NK cells from depletion in EAC omentum. Fractalkine promotes cytokine production and a CX3CR1⁻CD27⁺ phenotype in NK cells.