Improving the efficacy of natural killer cells for cancer therapy
NK cells exhibit direct cytotoxic function and are known to control the progression of cancer cells. This takes place through a mechanism known as antibody-dependent cellular cytotoxicity ADCC, by which NK cells attack cells coated with antibodies. However, tumour escape mechanisms reduce NK cell survival and/or functionality, hampering the use of NK cell-based immunotherapy in cancer treatment.
Improving NK cell function and survival
To develop strategies that improve anti-tumour responses and reduce NK cell exhaustion, scientists with the CINK project investigated the mechanisms by which NK cell activation is regulated. The research was undertaken with the support of the Marie Skłodowska-Curie (MSC) programme and focused on strategies that combine stimulating and/or inhibitory signals. “We evaluated a variety of strategies in order to improve the adoptive transfer of NK cells as an anti-cancer strategy,” says Pedro Berraondo, team leader at CIMA, University of Navarra, which hosted the project. One of the strategies followed by the MSC research fellow Maite Álvarez was to inhibit immune checkpoint mechanisms and assess their impact on NK function. One such key mechanism involves the interaction of the programmed cell death-1 (PD-1) receptor expressed on the surface of activated T cells and the ligands, PD-L1 and PD-L2, expressed on the surface of dendritic cells or macrophages. Under physiological conditions, this interaction serves as a co-inhibitory signal to limit T cell responses and avoid autoimmune inflammation. However, tumour cells overexpress PD-L1 and directly deactivate tumour-infiltrating T cells, evading T-cell mediated killing. CINK scientists neutralised PD-1 or PD-L1 with antibodies and observed an improvement in NK cell activation and function, concomitant with lower exhaustion. Moreover, they generated a novel methodology for expanding activated NK cells through the combinatorial use of Interleukin-15 and Apolipoprotein A1. Implementation of this strategy to generate activated NK cells for adoptive transfer directly in the tumour generated promising results in mouse models of colon cancer and metastatic melanoma.
Taking NK cells to the next stage
Cancer immunotherapy trials have highlighted various complications associated with tumour evasion mechanisms, an immunosuppressive tumour microenvironment as well as treatment-related toxicity. Collectively, they seem to prohibit effective and sustainable anti-cancer immune responses, pressing scientists to revisit basic immune concepts. The intrinsic self-regulatory mechanisms that govern NK cell activation have proved more complex than initially envisioned, often leading to an exhaustion phenotype. The CINK scientific team investigated NK cell biology and explored different approaches to induce a stronger and sustained NK cell activation and function, paving the way for the adoptive transfer of these cells. CINK results can also help towards the engineering of NK cells to express chimeric antigen receptors (CARs) against tumour cells similar to their CAR T cell counterparts. “CAR NK cells offer certain advantages over CAR T cells and can thus be used as off-the-shelf cellular drugs,” explains Berraondo. The CINK line of research will continue thanks to the support of the Spanish Association Against Cancer, AECC which granted Álvarez an investigator award. Activities will include a clinical trial to test the adoptive transfer of activated NK cells from a haploidentical donor in breast cancer patients pre-treated with anti-tumour antibodies.
Keywords
CINK, NK cells, immunotherapy, cancer, PD-1, PD-L1, apolipoprotein A1, CAR