Cancer is, evidently, an age-related disease. The immune system becomes less able to prevent precancerous cells from progressing to form a cancer. The burden of mutational damage is higher, increasing the odds of a cancerous combination of mutations arising. Lingering senescent cells pump out pro-growth, pro-inflammatory factors that make tissues more hospitable to growth of cancerous cells. Aging doesn't just affect the odds of cancer, however. The damage and dysfunction of aging induces changes in the behavior of cancer cells and progression of cancer that one might reasonably expect to be just as large and significant as the changes inflicted by aging upon normal cells and tissue function.
In today's open access editorial, researchers consider the intersection between mechanisms of aging and the progression of cancer. Extremely old people differ from younger old cohorts in important ways, including a more advanced decline of immune function, important to the way in which immunotherapies interact with cancerous tissues, and a greater burden of senescent cells, altering the tissue microenvironment with their secretions. Immunotherapies are on their way to eventually becoming the dominant form of cancer therapy, and in their best implementations represent a major advance over chemotherapeutics. As ever more of the standard treatments for forms of cancer become immunotherapies, there will be an ever greater interest in the fine details of interaction between cancer and the aging of the immune system and tissue microenvironment.
Aging and Cancer-Inextricably Linked Across the Lifespan
As patients age, several factors evolve that can profoundly influence cancer progression and responses to therapies. These factors include immune system changes, environmental exposures over a lifetime (exposome), frailty, the cumulative impact of stress (i.e., allostatic burden), comorbidities, and the varying degrees of physical and psychosocial resilience that come with aging and lived experiences. Additionally, a patient's treatment history and the secondary effects of those treatments on organ function play a crucial role in determining the efficacy of future therapies and could be pivotal in tailoring treatment options.
Hematological indications such as leukemias and lymphomas are more readily accessible for such analyses relative to solid tumor indications and represent powerful opportunities to understand the evolutionary process of therapeutic resistance. Notably, the age-dependent expansions of clones (often bearing cancer-associated mutations) in our tissues, which are associated with both malignant and nonmalignant disease risk as shown for the hematopoietic system, still represent a relatively unexplored frontier, particularly regarding the impact of these clonal expansions on patient responses to therapies and overall well-being.
Because the immune system undergoes change throughout the life course (e.g., age-related decline in naïve CD8+ T cells and expansion/exhaustion of memory phenotypes; increasing presence of GMZK+ CD8+ T cells; and biased expansion of myeloid-to-lymphoid cells) the function of immunotherapies such as checkpoint inhibitors and CAR-T cells, as well as immune-related adverse events, may vary accordingly. In infants and children, while CAR T cells have demonstrated success for B-cell acute lymphocytic leukemias, immune checkpoint inhibitor therapies have been less effective, likely due to the low mutation burden of pediatric cancers. Older and geriatric adults who are experiencing immune systemic and cellular senescence changes associated with aging still exhibit responses to checkpoint inhibitors, and CAR-T cell therapy can still be effective against B-cell lymphomas, albeit with reduced responses in those over 75. For older persons, factors such as prior antigen exposure and overall health status should clearly play roles but currently are understudied.
Additional immunotherapeutic opportunities include identifying approaches to limit the accumulation of senescent cells and exhausted cells; limiting genotoxic stress and radiation treatment induced DNA damage and senescence; as mentioned earlier, overcoming tissue contextual changes in the extracellular matrix within the tumor microenvironment that often limit access to tumors; adapting immunotherapies given the age-related increases in PD1 expression on T cells and age-related changes in metabolites (e.g., methylmalonic acid); and anticipating treatment-related complications and comorbidities, such as frailty.
Further to this point, aging is often accompanied by the accumulation of both subclinical and clinical comorbid conditions, which can alter treatment responses and influence disease progression. Different comorbidities (e.g., metabolic disease, cardiovascular disease, inflammatory syndromes) can modulate the pathophysiology of cancer through shared risk factors and biological pathways such as inflammation and immune function. Therefore, acknowledging and addressing these comorbidities is essential in crafting effective, patient-specific treatment plans.
View the full article at FightAging
