Dr Lisa Mielke
Immune checkpoint blockade is an emerging treatment in mismatch repair-deficient (dMMR) tumours for non-metastatic colorectal cancer that could help improve patient outcomes at an earlier stage, a cancer researcher says.
Speaking in a webinar held by the VCCC Alliance, Melbourne, Dr Lisa Mielke said currently a small subset of patients with metastatic disease and dMMR tumours were treated with immune checkpoint blockade – anti-PD-1 and anti-CTLA-4.
A laboratory head at the Olivia Newton-John Cancer Research Institute and La Trobe Institute for Molecular Science, Dr Mielke is investigating whether use of the therapies could be broadened to a wider group of patients.
She said already clinical trials had shown that neoadjuvant immunotherapy could lead to pathological responses in some proficient mismatch repair (pMMR) and all dMMR early-stage colon cancers as well as a 100% clinical response rate in rectal cancer with dMMR tumours.
“Around 20% of [colorectal cancer] patients with pMMR disease responded [in one of the trials] and traditionally, it was thought that these patients wouldn’t respond to the treatment…and so this result has sparked a number of other clinical trials and the broadening of this trial,” Dr Mielke told webinar viewers on 22 April.
Dr Mielke said studies also highlighted that the presence of high tumour infiltrating lymphocytes (TILs) predicted good survival outcomes irrespective of MMR status.
While CD8+ T cells were known to be important in defence against colorectal cancer, Dr Mielke said they became exhausted and less efficient as killer cells due to the chronic nature of the disease, however recent research showed Tpex cells could self renew and differentiate into exhausted T cells to eliminate tumours.
She said Tpex cells were therefore critical for maintaining and sustaining a robust CD8+ T cell response in tumours responding to immune checkpoint blockade, which now appeared to be an emerging treatment for early stage dMMR disease.
Meanwhile, Dr Mielke and her team’s findings demonstrated stage 3 colorectal cancer patients with a high abundance of TCF-1 expressing CD8+ cells within their tumours had better disease-free survival and overall survival outcomes.
Her team also conducted an immune cell location analysis of pMMR and dMMR stage 3 tumours, which showed that Tpex cells were more highly abundant within the lymphoid aggregates than the tumour stroma, whereas effector and exhausted T cells were evenly distributed throughout the different regions of the tumour.
“What was really interesting about these results is that when we compared the patients that had the dMMR or the pMMR tumours, we didn’t find much of a difference between the number of Tpex cells in lymphoid aggregates… that suggests that potentially patients would respond equally to immunotherapy.”
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Dr Mielke also found that TCF-1 positive gamma delta T cells had lower expression of the functional genes XCL1 and Granzyme B in colorectal cancer, which had been shown to be important for killing tumour cells. Whereas the TCF-1 negative gamma delta T cells had a very high expression of these genes.
Lack of TCF-1 expression marked an effector population of gamma delta T cells.
Her findings also identified TCF-1 positive gamma delta T cells in the normal epithelium surrounding the tumour, which could express PD-1 or PD-1 negative.
“The TCF-1 expression, or the ratio of TCF-1 positive to negative T cells, is reduced in colorectal cancer within the tumours but also interestingly within the normal colon tissue surrounding the tumours, and so that really suggested to us that these cells are able to recognise or respond to factors in their environment to change expression of TCF-1,” Dr Mielke told the audience.
Dr Mielke said the next steps were to investigate the factors controlling TCF-1 expression and whether these factors could be downregulated for gamma delta T cells to become more effective at killing tumour cells, as well as looking at how TCF-1 and immune checkpoint blockade control effector functions of these cells.