The extent to which a tumour is infiltrated with immune cells can determine the outcome of immunotherapy. Now, Li et al. report that tumour cell-intrinsic factors underlie the heterogeneity in the immune landscape of tumours as well as the response to immunotherapy of pancreatic ductal adenocarcinoma (PDA).
Quantification of CD8+ T cells and total T cells in resected tumours from patients with PDA and those from a mouse model of PDA (KPC mice) showed that T cell abundance varied greatly: tumours could be categorized as ‘T cell high’ (T cellhi) or ‘T cell low’ (T celllow). After establishing a library of congenic tumour cell clones from a collection of mouse PDAs, individual clones were implanted into healthy mice and the tumours they formed had similar immune microenvironments to the tumours from which they were derived, indicating that the tumour immune microenvironment is transplantable. Interestingly, T cellhi tumours tended to have a higher number of dendritic cells (DCs) and a lower number of myeloid cells than T celllow tumours. Further analysis revealed that the difference in immune cell infiltration was likely not due to the mutational burden, site of injection or host microbiome.
The authors then determined whether the difference in T cell infiltration influenced the response of primary tumours to a chemotherapy–immunotherapy combination — T celllow tumours were minimally affected, whereas mice with T cellhi tumours had improved survival and their tumours showed marked regression. Most (75%) T cellhi tumours were cleared by combination therapy, whereas no T celllow tumours were cleared. Importantly, when mice cured of a T cellhi tumour were challenged with a different T cellhi clone or with a T celllow clone, tumour growth was reduced by combination therapy, suggesting that tumour clones have shared tumour antigens that are recognized by infiltrating T cells.
Next, the authors analysed the immune cell populations of T cellhi and T celllow tumours. CD8+ T cells in T cellhi tumours had higher expression of markers of activated or antigen-experienced T cells, such as PD1, CD44, LAG3, CTLA4, TIM3 and NUR77, than those in T celllow tumours, although functional activity was not higher. For clones with similar T cell infiltration levels, the efficacy of combination therapy correlated with the proportion of PD1+CD8+ T cells in the tumours they formed, suggesting that this proportion determines the response to combination therapy.
Cross-presenting (CD103+) DCs are crucial for tumour immunity and, indeed, their abundance correlated with CD8+ T cell number across tumour clones. Importantly, PDA tumours established in mice lacking CD103+ DCs almost completely lacked CD8+ T cells. Further analysis suggested that CXCR3 was necessary for bulk CD8+ T cell recruitment to tumours, but PD1+CD8+ T cells were present and able to drive tumour responses after therapy when used in combination with CXCR3 blockade. Additionally, T celllow tumours promoted an increase in circulatory myeloid cells, although contralateral injection experiments established that the systemic factors presumably responsible for this expansion did not alter the tumour microenvironment (TME) of T cellhi tumours. By contrast, co-injection of T cellhi and T celllow clones at the same site showed that T celllow tumour cells acted dominantly to locally suppress T cell infiltration into the tumour.
As secreted factors seemed to mediate immune suppression, examination of chemokine expression established that Cxcl1 was the most differentially expressed chemokine in T cellhi and T celllow tumours, which was shown by epigenomic analysis to be due to a more accessible Cxcl1 promoter region and enrichment of an active histone mark in T celllow tumour cells. Further experiments suggested that tumour cell-derived CXCL1 promotes the recruitment of suppressive myeloid cells into tumours, which suppresses T cell infiltration, contributing to immunotherapy resistance.
“tumour cell-derived CXCL1 promotes the recruitment of suppressive myeloid cells into tumours, which suppresses T cell infiltration”
Finally, the authors identified additional factors (for example, CSF3) that affect immune cell infiltration into the TME. Their new experimental system should prove highly useful for identifying additional mechanisms underlying tumour immune heterogeneity.
Li, J. et al. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity. https://doi.org/10.1016/j.immuni.2018.06.006 (2018)
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Otto, G. Tumour decides immune cell ins and outs. Nat Rev Immunol 18, 481 (2018). https://doi.org/10.1038/s41577-018-0038-y
Frontiers in Immunology (2019)