Table 1

Primary tumour prognostic and predictive IHC-based TIME biomarkers in patients receiving chemotherapy

Immune biomarkerLocationPrognostic role in early stage patients receiving adjuvant chemotherapy (regime)Prognostic role in stage IV patients receiving palliative chemotherapy (regime)Predictive role or differential biomarker prognostic role by treatment group
Specific immune cell
CD3+ CTMost studies - î density=positive prognostic assoc

  • Improved OS36 40 42 43 and DFS41 (5-FU)

  • Improved DFS (FOLFOX)44 45

    Few studies – no association

  • OS (unspecified regimes)46 and DFS (5-FU+/-bevacizumab)47

î density=positive prognostic assoc

  • Improved OS (unspecified regimes)55

Possible negative predictive role (adjuvant chemotherapy unspecified)

  • î density (vs low density)=improved OS in observation group (not chemotherapy group)46

IMî density=mixed findings

  • No association DFS48 or OS40 (5-FU)

  • Improved DFS44 45 and OS49 (FOLFOX)

î density=positive prognostic assoc

  • Improved OS (unspecified regimes)55

CD8+ CT (CS)Most studies - î density=positive prognostic assoc

  • Improved OS42 46 50 and DFS47 51 (5-FU)

  • Improved DFS44 45 52 (FOLFOX)

    Few studies – no association

  • OS (5-FU)40

î density=mixed findings

  • Improved OS (oxal/irinotecan+5-FU)54

  • No assoc OS (unspecified regime55 and FOLFOX)56

No predictive role (adjuvant 5-FU)

  • î density=improved OS in patients treated with and without adjuvant chemotherapy46

IMMost studies - î density=positive prognostic assoc

  • Improved OS (5-FU)53

  • Improved DFS (FOLFOX,45 CAPOX)52

    Few studies – no association

  • OS (5-FU,40 unspecified regime)71

No prognostic assoc

  • OS (unspecified regime)55

Possible positive predictive role (adjuvant 5-FU)

  • î density (vs low density)=OS benefit greater for patients treated with adjuvant chemotherapy>observation53

CD4+ CTî density=mixed findings

  • Improved OS (unspecified regimes)55

  • No association OS (FOLFOX)56

IMî density=positive prognostic assoc

  • Improved OS (unspecified regimes)55

Immunoscore
(CD3+ and CD8+ CT + IM)		0–4High score=positive prognostic assoc

  • Improved DFS high-risk stage II (5-FU)65

  • Improved DFS stage III (FOLFOX)45 63

  • Improved OS stage III (5-FU,33 62 variable regimes)64

Positive predictive role stage III (various adjuvant regimes)

  • High IS (2-4)=DFS benefit with adjuvant chemotherapy (vs low IS 0–1—no benefit)64


Not predictive stage II (adjuvant 5-FU)65
Foxp3+ (Treg)CTî density=mixed findings

  • Improved OS (5-FU)40 42 46 50

  • No association DFS (5-FU)41

  • Worse DFS/OS (unspecified regime)70

î density=mixed findings

  • Improved OS (FOLFOX,56 5-FU+oxaliplatin or irinotecan)54

  • No association OS (unspecified regime)55

Mixed findings

  • Not predictive (adjuvant 5-FU)46

  • Possible negative predictive role (adjuvant chemotherapy unspecified)

    • î density (vs low density)=worse OS/DFS in adjuvant chemotherapy group (not observation group)70

IMNo prognostic association

  • DFS/OS on multivariate analysis (unspecified regime)71

No prognostic association

  • OS (unspecified regime)55

Possible negative predictive role (adjuvant chemotherapy unspecified)

  • î density (vs low density)=improved OS in observation group (not chemotherapy group)71

CD66b+ (TAN)CTî density=positive prognostic association

  • Improved DFS/OS (5-FU,74 unspecified regime)70

Mixed findings

  • Possible negative predictive role (adjuvant chemotherapy unspecified)

    • î density=no OS/DFS benefit from adjuvant chemotherapy (vs observation); vs low density—possible OS/DFS detriment with adjuvant chemotherapy70

  • Positive predictive role (adjuvant 5-FU)

    • î density (vs low density)=improved DFS in adjuvant chemotherapy group; vs worse DFS in observation group74

IMî density=positive prognostic association

  • Improved DFS (5-FU)75

Possible positive predictive role (adjuvant 5-FU)

  • î density (vs low density)=improved DFS in chemotherapy group only (not observation group)75

CD68+ (general TAM marker)CTNo prognostic assoc stage II

  • DFS/OS (5-FU)77

î density=negative prognostic association

  • Worse OS (unspecified regimes)55

IMî density=positive prognostic association

  • Improved DFS (5-FU)75

No prognostic association

  • OS (unspecified regime55

Possible positive predictive role (adjuvant 5-FU)

  • î density (vs low density)=improved DFS in chemotherapy group (not observation group)75

CD163+ (M2 polarised TAM)CTî density=negative prognostic association

  • Worse DFS/OS (unspecified regime)70

î density=negative prognostic association

  • Worse OS (unspecified regimes)55

Possible negative predictive role (unspecified adjuvant regime)

  • î density (vs low density)=worse DFS in chemotherapy group (not observation group)70

IMNo prognostic association

  • OS (unspecified regime)55

CD206+ (M2 polarised TAM)CTî density=negative prognostic association

  • Worse DFS/OS (5-FU)77

Possible positive predictive role (adjuvant 5-FU)

  • î ratio CD206+:CD68+ = improved DFS with adjuvant chemotherapy (vs low ratio—no benefit)77

CD45RO+ (memory T cell)CTî density=positive prognostic association

  • Improved OS (5-FU)42 43

î density=positive prognostic association

  • Improved OS (oxal/irinotecan+5-FU)54

IMî density=positive prognostic association

  • Improved OS (unspecified regime)71

No predictive role (adjuvant chemotherapy unspecified)

  • î density=improved OS in patients treated with and without adjuvant chemotherapy71

  • CS, core tumour stroma; CT, core tumour; DFS, disease-free survival; 5-FU, 5-fluorouracil; IHC, immunohistochemical; IM, invasive margin; OS, overall survival; TAM, tumour-associated macrophage; TAN, tumour-associated neutrophil; TIME, tumour immune microenvironment; TLS, tertiary lymphoid structures.