The immune system is a major determinant of how patients respond to standard treatments for ovarian cancer, the leading cause of death from gynaecological malignancies.

But little was known about how the immune landscape of tumours changes when patients relapse—as they frequently do—or how those changes influence responses to subsequent therapy, which tend to be dismal.

This is no longer the case.

A comparative analysis of the immune milieu of primary and recurrent ovarian tumours, the largest study of its kind so far, has shed much-needed light on both these questions and, in doing so, uncovered new strategies for ovarian cancer therapy.

Led by Ludwig Lausanne’s Denarda Dangaj Laniti and Eleonora Ghisoni and reported in the current issue of Cancer Cell, the study defines four different immunologic subtypes of recurrent ovarian cancers and describes how those subtypes are related to a key genomic characteristic of host tumours.

The researchers also detail how the gene expression and immune landscape of each evolve upon relapse to drive therapeutic resistance.

“Our study combined digital pathology of hundreds of human tumour samples with preclinical studies in mouse models to crack the immune code of ovarian cancer and develop a simple classification tool for the malignancy that could have powerful applications in the clinic,” said Dangaj Laniti.

“With additional vetting in clinical studies, our classification system could serve as a combined immunologic and genomic biomarker to improve the personalisation of ovarian cancer therapy.”

To develop and validate their classification system, the researchers analysed a total of 697 primary and recurrent tumour samples from five independent clinical cohorts.

The immune classifier they developed—based on the degree to which tumours were infiltrated with the immune system’s CD8 + T lymphocytes, the primary killers of cancer cells—assigned tumours to one of four immunologic buckets.

Those extensively or moderately infiltrated with T lymphocytes were classified respectively, as “purely inflamed” or “mixed-inflamed” tumours, while those with T cells only on their periphery or with no T lymphocytes to speak of were categorised as “excluded” or “desert” tumours.

The researchers found that patients with purely inflamed and mixed inflamed tumours tended to survive significantly longer than those with excluded and desert tumours.

Additionally, tumours whose cells bear mutations that disable their DNA repair machinery—such as the famous BRCA1 mutation—were more likely to be inflamed and most strongly associated with better overall survival following chemotherapy.

Tumours of mixed, excluded or desert subtypes, and those that were proficient in DNA repair, were less likely to be associated with long-term survival upon cancer recurrence.

But tumour-infiltrating T lymphocytes (TILs) are not the only immune cells involved in anti-tumour immune responses.

The immune system’s myeloid cells also help determine how resistant the tumour microenvironment is to anti-tumour immune responses (and are the subject of a concerted research initiative at Ludwig Lausanne, from which this study stems).

This includes dendritic cells, which help direct and prime the T cell assault on tumours.

Another myeloid cell, the macrophage, can similarly help orchestrate such T cell responses, but can also kill cancer cells itself or—if flipped into an alternate functional state—suppress anti-tumour immunity.

The researchers show that myeloid cells help reestablish the immune landscape of primary ovarian tumours when the cancer recurs.

Tumours proficient in DNA repair, which tend to be of the desert variety upon recurrence, produce proteins that draw relatively large numbers of immunosuppressive macrophages into their microenvironment.

These macrophages, the researchers report, are marked by their expression of proteins involved in lipid metabolism known as ApoE and Trem2.

Targeting myeloid cells in such tumours with an antibody inhibitor of Trem2 improved responses to chemotherapy and delayed tumour recurrence in mouse models.

Purely inflamed tumours with DNA repair deficiency, meanwhile, house networks of TILs and dendritic cells that have been shown by Ludwig Lausanne researchers to be essential to effective anti-tumour immunity and immunotherapy in ovarian cancer and melanoma.

The researchers found that these niches persist upon disease recurrence and even draw in anti-tumour macrophages to support immune responses.

So how do these tumours evade immune clearance?

Experiments revealed that the cancer cells of inflamed tumours respond to a standard combination of chemotherapy and olaparib—a drug used to treat BRCA-deficient ovarian cancer—by activating a molecular signalling pathway driven by an enzyme known as COX.

The pathway induces the secretion of PGE2, a lipid that functionally disables and induces the suicide of TILs.

Treating mice bearing inflamed, DNA repair-deficient tumours with an existing COX-inhibitor along with olaparib and chemotherapy significantly extended survival.

That survival time doubled when this combination was supplemented with checkpoint blockade immunotherapy, which activates anti-tumour TILs.

“Our findings have immediate and testable implications for the treatment of ovarian cancer,” said Ghisoni.

“They suggest that patients with inflamed, DNA repair-deficient tumours may be ideal candidates for immunotherapy trials, while those with suppressive tumours may benefit from new therapeutic strategies, like TREM2 inhibition.”

More generally, the findings underscore the importance of targeting both cancer cells and the immune cells that enable immune evasion.

Source: Ludwig Institute for Cancer Research