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Lo Re et al. J Cancer Metastasis Treat 2019;5:81 I http://dx.doi.org/10.20517/2394-4722.2019.30 Page 5 of 8

The emerging difficulties derive from the possible hormonal role on the total NK count, which does not
include the tissue one, and from the correlations with performance status, age, and disease status in acute
[20]
and chronic exercise .
Regarding innate immunity, immunological differences between healthy persons and cancer patients
have been demonstrated [21,22] . In healthy persons, exercise can positively influence the pro-inflammatory
[22]
[21]
polarization of M1 macrophages following immune escape , and neutrophil counts , while, in a tumor
animal model, exercise caused vascular normalization and hypoxia reduction with improvement of
[23]
response to chemotherapy and reduction of TAMs and neutrophils infiltrating their tumors determining
[24]
tumor volume reduction .
In the adaptive immune response, Th1-polarized T cells and Tregs, influenced by adhesion molecules,
are involved in maintaining peripheral tolerance and appear to have a prognostic role [25-27] . Moderate-
intensity exercise produced in healthy 65-year-old subjects a greater increase in lymphocyte response to
[28]
immunogenic stimulation than in those who performed flexibility and toning exercises . In fact, a single
bout of physical exercise also seems to determine in the healthy an increase of differentiated NK-cells,
CD8+, and ϫδ T-cells, with marked sensitivity to external stimulation. This could have an implication
in hematopoietic stem cell transplantation and represent a valid aid in the conventional treatment of
[29]
tumors .
Reduction of leukocyte count, improvement of depressive symptoms, and increase in diurnal salivary
cortisol rhythm can be obtained in patients with a six-month exercise program differently from in
[18]
sedentary patients but without the lymphocyte functional finding .
Finally, in low immunogenic tumors, such as pancreatic adenocarcinoma, chemotherapy with drugs such
[30]
as anthracyclines can trigger an immune response through dendritic cells (DC) .
Similar to chemotherapy, marathon running increases myeloid DC counts and the production of pro-
[31]
and anti-inflammatory cytokines . This finding supports the role of immunomodulatory mechanisms in
the response and adaptation to acute, excessive exercise. The possible clinical application of these results
has found a clinical finding in pretreated, unresponsive patients and in progression of disease, obtaining
a disease control rate of 41%, improvement of physical status, reduced risk of progression, and impact on
[32]
increase of cytotoxic CD8+ CD28+ and decrease of suppressive CD8+ CD28- T cell .

Regarding long-term survivors, the increased risk of developing second cancers and cardiovascular
complications is known.

In this case, it also seems that the amplitude of physical activity reduced the risk of both cancer-related
[11]
[12]
mortality and cardiovascular disease . However, this was not found in PDAC .
Nevertheless, there is some evidence for correlations among antiblastic treatment, moderate but constant
physical exercise, and immune response in the neoplastic patients, although knowledge about the impact of
physical activity on the immune system is not conclusive.

Cell death by chemotherapy might not be the single modality of antitumor action; there may be other
immunomodulation mechanisms, regulated and controlled by immunosuppressive cells, that can condition
the therapeutic response. They could act as an additive to chemotherapy and could improve the therapeutic
index if “physical conditioning exercise” has been administered in selected patients before starting
chemotherapy or new innovative therapy with checkpoint inhibitors.