We attended this year’s annual meeting of The Association for Molecular Pathology. It was a virtual meeting that took place on 16th – 20th November 2020. The event was a fantastic opportunity to hear from leading experts in the field of cancer research. In particular, we enjoyed the talks by Dr Thomas Gajewski (University of Chicago) and Dr Scott Rodig (Brigham and Women’s Hospital) .
You can read our summaries of these two talks below:
Integrative Analysis of the Tumour Microenvironment: Anti-PD1-based immunotherapy and the role of the microbiota
A talk by Dr Thomas Gajewski, University of Chicago
T-cells are a key component of cellular immune responses. T-cells act through the recognition of a ‘non-self antigen’, in the context of MHC, (via an antigen presenting cell or by the tumour itself). However, T-cell activation can be inhibited by the PD1/PDL1/PDL2 pathway, thus, anti-PD1 based immunotherapy has been developed.
What are the mechanisms of efficacy for these treatments? And when they fail, what are the mechanisms of resistance?
Dr Gajeski described a recent discovery that a major subset of patients with solid tumours have, at baseline, evidence of an endogenous immune response. In other words, they demonstrated a T-cell inflamed microenvironment. These patients were readily expressing chemokines, some CD8+ T-cells specific to the tumour and type I interferon signature which relates to the innate immune response. So why were these tumours not rejected immediately if there is already an immune response mounted against them? Malignant cells can induce negative regulatory pathways, inhibitory processes that shut down T-cells by immune regulation or inhibition processes.
Why do some patients have a T-cell inflamed tumour microenvironment but not others?
There are several key components for an inflamed tumour microenvironment. Firstly, type I interferon signalling is upstream of T-cell activation and necessary to set up this microenvironment. Secondly, a specific lineage of dendritic cells (the Batf3-lineage) are needed for T-cell priming. These dendritic cells are also required to produce chemokines that attract activated T-cells back to the tumour. However, the activation of beta-catenin within these tumour cells inhibits the host anti-tumour response and causes a failure to recruit this dendritic subset.
These dendritic cells are also required to be present at the onset of anti-PD1 therapy in order to facilitate successful tumour regression. The efficacy of PD1 blockade therapy is dependent on interactions between these dendritic cells and CD8+ T-cells in the tumour microenvironment. Therefore, therapies which block PD1 in tumours and use dendritic cells to reinvigorate T-cells are currently being investigated in clinical trials.
Interestingly, Dr Gajeski reported that CD8 T-cells and dendritic cells seem to colocalise within the tumour. T-cells appear to cluster to the DCs, and top responders to anti-PD1 therapies are those patients who exhibit the highest colocalization.
Why do some patients not generate this T-cell inflamed microenvironment?
There are several factors which influence patient immune responses. Somatic differences at the level of tumour cells such as Wnt/Beta Catenin activation can alter these responses. Furthermore, germline genetic differences at the level of the host such as polymorphisms in immune regulatory genes can also impact responses. However, a key factor is environmental differences, specifically in the gut microbiota of patients.
Dr Gajeski described distinct microbiota in anti-PD1 responders and and in non-responder melanoma patients. In fact, he suggested it may be the most rate limiting step for anti-PD1 efficacy. His study also found that this impact was preserved over generations, propagated almost as a genetic trait except it is a purely environment factor. They found that sterile mice which are reconstituted with the faeces non-responders become non-responders and vice versa. Importantly, it was also found this can be corrected through a fecal transplant from responder mice.
Favourable microbiota have also been shown to have more M1 macrophages in TME, whereas a less favourable microbiota lead to a M2 macrophage gene expression profile. These macrophages are less tumoricidal and have an immune regulatory function. Strategies to manipulate the microbiota are being explored and there are several clinical trials underway.
Tumours are Immunogenic: The role of PD1 and CTLA4 in Hodgkin Lymphoma
A talk by Dr Scott Rodig, Brigham and Women’s Hospital
In many cases of early cancer, tumours are recognised and removed by the immune system before they can develop. Cancers can be cold, with little to no immune cell infiltrate, warm or hot, with heavy immune infiltrate. Warm and hot tumours contain immune cells which recognise antigens produced by the tumour, but tend to be ineffective at removing the neoplasm.
Hodgkin Lymphoma is a rare type of cancer. Here, malignant cells are a minority within the tumour microenvironment (1-5%). In fact, the rest of the cells are non-neoplastic inflammatory cells. Hodgkin Reed-Sternberg cells (HRS cells) express 2 different ligands – CD86 and PDL1. In Hodgkin Lymphoma, T-cell activation is inhibited by the PD1/PDL1/2 pathway and the CTLA4/CD80/CD86 signalling pathway.
Dr Rodig explained how his team were able to characterise the tumour microenvironment, using a quantitative assay of automated staining, coupled with an image analysis system. Within the tumour microenvironment, they observed that PDL1 is highly expressed by HRS cells, as well as by tumour-associated macrophages (TAMs) in the vicinity of these HRS cells. Therefore, they hypothesised that non-neoplastic macrophages in the tumour microenvironment are major contributors to PDL1 production, producing an immunosuppressive tumour microenvironment.
They also observed that the tumour microenvironment is polarised. It has an increased density of PDL1+ macrophages and PDL1+ T-cells observed in the vicinity of malignant HRS. This led to the development of the castle and moat hypothesis, which describes how neoplastic HRS cells protect themselves by expressing immunosuppressive ligands and also form a protective layer of immune cells which do the same.
Dr Rodig suggested that these types of tumours should be uniquely susceptible to PD1-blockade therapies. He quoted a recent case study of a patient who had been heavily pre-treated, had failed multiple lines of therapy and had recently relapsed. They administered this patient with anti-PD1 therapy (Nivolumab) and within 6 weeks, all tumours had shrunk from baseline. Dr Rodig suggests this therapy will prove highly effective in patients with relapsed/refractory disease.
The CTLA4/CD80/CD86 pathway also leads to the inhibition of T-cell activation. When blocked, T-cell signalling can be restored. HRS cells and TAMs express high levels of the ligand CD86. Additionally, CTLA4 expressing T-cells are enriched in the vicinity of HRS (tumour) cells and macrophages. Together, this produces a highly immunosuppressive local tumour microenvironment.
HRS cells engage with 2 different types of T-cells: CD4+ T-cells and PD1+ T-cells. Both exist within a niche surrounding the malignant cells. Could anti CTLA4-based therapies be effective in patients that fail anti-PD1 treatment? Or could a combination of both prove more effective? Clinical trials are currently underway to investigate these hypotheses.
Image credit: By Mohammed Haneefa Nizamudeen – canva.com